Author: "Natalia Antonenkova" - Searchworks@Jio Institute Digital Library Search Results

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1. Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility.

Author: Madalene Earp, Jonathan P Tyrer, Stacey J Winham, Hui-Yi Lin, Ganna Chornokur, Joe Dennis, Katja K H Aben, Hoda Anton-Culver, Natalia Antonenkova, Elisa V Bandera, Yukie T Bean, Matthias W Beckmann, Line Bjorge, Natalia Bogdanova, Louise A Brinton, Angela Brooks-Wilson, Fiona Bruinsma, Clareann H Bunker, Ralf Butzow, Ian G Campbell, Karen Carty, Jenny Chang-Claude, Linda S Cook, Daniel W Cramer, Julie M Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Evelyn Despierre, Jennifer A Doherty, Thilo Dörk, Andreas du Bois, Matthias Dürst, Douglas F Easton, Diana M Eccles, Robert P Edwards, Arif B Ekici, Peter A Fasching, Brooke L Fridley, Aleksandra Gentry-Maharaj, Graham G Giles, Rosalind Glasspool, Marc T Goodman, Jacek Gronwald, Philipp Harter, Alexander Hein, Florian Heitz, Michelle A T Hildebrandt, Peter Hillemanns, Claus K Hogdall, Estrid Høgdall, Satoyo Hosono, Edwin S Iversen, Anna Jakubowska, Allan Jensen, Bu-Tian Ji, Audrey Y Jung, Beth Y Karlan, Melissa Kellar, Lambertus A Kiemeney, Boon Kiong Lim, Susanne K Kjaer, Camilla Krakstad, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D Le, Shashi Lele, Jenny Lester, Douglas A Levine, Zheng Li, Dong Liang, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Iain McNeish, Usha Menon, Roger L Milne, Francesmary Modugno, Kirsten B Moysich, Roberta B Ness, Heli Nevanlinna, Kunle Odunsi, Sara H Olson, Irene Orlow, Sandra Orsulic, James Paul, Tanja Pejovic, Liisa M Pelttari, Jenny B Permuth, Malcolm C Pike, Elizabeth M Poole, Barry Rosen, Mary Anne Rossing, Joseph H Rothstein, Ingo B Runnebaum, Iwona K Rzepecka, Eva Schernhammer, Ira Schwaab, Xiao-Ou Shu, Yurii B Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C Southey, Beata Spiewankiewicz, Lara Sucheston-Campbell, Ingvild L Tangen, Soo-Hwang Teo, Kathryn L Terry, Pamela J Thompson, Lotte Thomsen, Shelley S Tworoger, Anne M van Altena, Ignace Vergote, Liv Cecilie Vestrheim Thomsen, Robert A Vierkant, Christine S Walsh, Shan Wang-Gohrke, Nicolas Wentzensen, Alice S Whittemore, Kristine G Wicklund, Lynne R Wilkens, Yin-Ling Woo, Anna H Wu, Xifeng Wu, Yong-Bing Xiang, Hannah Yang, Wei Zheng, Argyrios Ziogas, Alice W Lee, Celeste L Pearce, Andrew Berchuck, Joellen M Schildkraut, Susan J Ramus, Alvaro N A Monteiro, Steven A Narod, Thomas A Sellers, Simon A Gayther, Linda E Kelemen, Georgia Chenevix-Trench, Harvey A Risch, Paul D P Pharoah, Ellen L Goode, and Catherine M Phelan
Subjects: Medicine, Science
Abstract: Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.
Published: 2018
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2. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology

Author: Linda E. Kelemen, Madalene Earp, Brooke L. Fridley, Georgia Chenevix-Trench, on behalf of Australian Ovarian Cancer Study Group, Peter A. Fasching, Matthias W. Beckmann, Arif B. Ekici, Alexander Hein, Diether Lambrechts, Sandrina Lambrechts, Els Van Nieuwenhuysen, Ignace Vergote, Mary Anne Rossing, Jennifer A. Doherty, Jenny Chang-Claude, Sabine Behrens, Kirsten B. Moysich, Rikki Cannioto, Shashikant Lele, Kunle Odunsi, Marc T. Goodman, Yurii B. Shvetsov, Pamela J. Thompson, Lynne R. Wilkens, Thilo Dörk, Natalia Antonenkova, Natalia Bogdanova, Peter Hillemanns, Ingo B. Runnebaum, Andreas du Bois, Philipp Harter, Florian Heitz, Ira Schwaab, Ralf Butzow, Liisa M. Pelttari, Heli Nevanlinna, Francesmary Modugno, Robert P. Edwards, Joseph L. Kelley, Roberta B. Ness, Beth Y. Karlan, Jenny Lester, Sandra Orsulic, Christine Walsh, Susanne K. Kjaer, Allan Jensen, Julie M. Cunningham, Robert A. Vierkant, Graham G. Giles, Fiona Bruinsma, Melissa C. Southey, Michelle A.T. Hildebrandt, Dong Liang, Karen Lu, Xifeng Wu, Thomas A. Sellers, Douglas A. Levine, Joellen M. Schildkraut, Edwin S. Iversen, Kathryn L. Terry, Daniel W. Cramer, Shelley S. Tworoger, Elizabeth M. Poole, Elisa V. Bandera, Sara H. Olson, Irene Orlow, Liv Cecilie Vestrheim Thomsen, Line Bjorge, Camilla Krakstad, Ingvild L. Tangen, Lambertus A. Kiemeney, Katja K.H. Aben, Leon F.A.G. Massuger, Anne M. van Altena, Tanja Pejovic, Yukie Bean, Melissa Kellar, Linda S. Cook, Nhu D. Le, Angela Brooks-Wilson, Jacek Gronwald, Cezary Cybulski, Anna Jakubowska, Jan Lubiński, Nicolas Wentzensen, Louise A. Brinton, Jolanta Lissowska, Estrid Hogdall, Svend Aage Engelholm, Claus Hogdall, Lene Lundvall, Lotte Nedergaard, Paul D.P. Pharoah, Ed Dicks, Honglin Song, Jonathan P. Tyrer, Iain McNeish, Nadeem Siddiqui, Karen Carty, Rosalind Glasspool, James Paul, Ian G. Campbell, Diana Eccles, Alice S. Whittemore, Valerie McGuire, Joseph H. Rothstein, Weiva Sieh, Steven A. Narod, Catherine M. Phelan, John R. McLaughlin, Harvey A. Risch, Hoda Anton-Culver, Argyrios Ziogas, Usha Menon, Simon A. Gayther, Aleksandra Gentry-Maharaj, Susan J. Ramus, Anna H. Wu, Celeste Leigh Pearce, Alice W. Lee, Malcolm C. Pike, Jolanta Kupryjanczyk, Agnieszka Podgorska, Joanna Plisiecka-Halasa, Wlodzimierz Sawicki, Ellen L. Goode, Andrew Berchuck, and Ovarian Cancer Association Consortium
Subjects: consortia, enolase superfamily member 1, expression quantitative trait locus, genetics, gynecology, ovarian neoplasms, single-nucleotide polymorphism, thymidylate synthase, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3′ gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97–1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03–1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10−28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
Published: 2018
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3. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk.

Author: Ganna Chornokur, Hui-Yi Lin, Jonathan P Tyrer, Kate Lawrenson, Joe Dennis, Ernest K Amankwah, Xiaotao Qu, Ya-Yu Tsai, Heather S L Jim, Zhihua Chen, Ann Y Chen, Jennifer Permuth-Wey, Katja K H Aben, Hoda Anton-Culver, Natalia Antonenkova, Fiona Bruinsma, Elisa V Bandera, Yukie T Bean, Matthias W Beckmann, Maria Bisogna, Line Bjorge, Natalia Bogdanova, Louise A Brinton, Angela Brooks-Wilson, Clareann H Bunker, Ralf Butzow, Ian G Campbell, Karen Carty, Jenny Chang-Claude, Linda S Cook, Daniel W Cramer, Julie M Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Andreas du Bois, Evelyn Despierre, Ed Dicks, Jennifer A Doherty, Thilo Dörk, Matthias Dürst, Douglas F Easton, Diana M Eccles, Robert P Edwards, Arif B Ekici, Peter A Fasching, Brooke L Fridley, Yu-Tang Gao, Aleksandra Gentry-Maharaj, Graham G Giles, Rosalind Glasspool, Marc T Goodman, Jacek Gronwald, Patricia Harrington, Philipp Harter, Alexander Hein, Florian Heitz, Michelle A T Hildebrandt, Peter Hillemanns, Claus K Hogdall, Estrid Hogdall, Satoyo Hosono, Anna Jakubowska, Allan Jensen, Bu-Tian Ji, Beth Y Karlan, Linda E Kelemen, Mellissa Kellar, Lambertus A Kiemeney, Camilla Krakstad, Susanne K Kjaer, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D Le, Alice W Lee, Shashi Lele, Arto Leminen, Jenny Lester, Douglas A Levine, Dong Liang, Boon Kiong Lim, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Iain McNeish, Usha Menon, Roger L Milne, Francesmary Modugno, Kirsten B Moysich, Roberta B Ness, Heli Nevanlinna, Ursula Eilber, Kunle Odunsi, Sara H Olson, Irene Orlow, Sandra Orsulic, Rachel Palmieri Weber, James Paul, Celeste L Pearce, Tanja Pejovic, Liisa M Pelttari, Malcolm C Pike, Elizabeth M Poole, Harvey A Risch, Barry Rosen, Mary Anne Rossing, Joseph H Rothstein, Anja Rudolph, Ingo B Runnebaum, Iwona K Rzepecka, Helga B Salvesen, Eva Schernhammer, Ira Schwaab, Xiao-Ou Shu, Yurii B Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C Southey, Beata Spiewankiewicz, Lara Sucheston, Soo-Hwang Teo, Kathryn L Terry, Pamela J Thompson, Lotte Thomsen, Ingvild L Tangen, Shelley S Tworoger, Anne M van Altena, Robert A Vierkant, Ignace Vergote, Christine S Walsh, Shan Wang-Gohrke, Nicolas Wentzensen, Alice S Whittemore, Kristine G Wicklund, Lynne R Wilkens, Anna H Wu, Xifeng Wu, Yin-Ling Woo, Hannah Yang, Wei Zheng, Argyrios Ziogas, Hanis N Hasmad, Andrew Berchuck, Georgia Chenevix-Trench, AOCS management group, Edwin S Iversen, Joellen M Schildkraut, Susan J Ramus, Ellen L Goode, Alvaro N A Monteiro, Simon A Gayther, Steven A Narod, Paul D P Pharoah, Thomas A Sellers, and Catherine M Phelan
Subjects: Medicine, Science
Abstract: BACKGROUND:Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. METHODS:In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q
Published: 2015
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4. Mutation analysis of the ERCC4/FANCQ gene in hereditary breast cancer.

Author: Sandra Kohlhase, Natalia V Bogdanova, Peter Schürmann, Marina Bermisheva, Elza Khusnutdinova, Natalia Antonenkova, Tjoung-Won Park-Simon, Peter Hillemanns, Andreas Meyer, Hans Christiansen, Detlev Schindler, and Thilo Dörk
Subjects: Medicine, Science
Abstract: The ERCC4 protein forms a structure-specific endonuclease involved in the DNA damage response. Different cancer syndromes such as a subtype of Xeroderma pigmentosum, XPF, and recently a subtype of Fanconi Anemia, FA-Q, have been attributed to biallelic ERCC4 gene mutations. To investigate whether monoallelic ERCC4 gene defects play some role in the inherited component of breast cancer susceptibility, we sequenced the whole ERCC4 coding region and flanking untranslated portions in a series of 101 Byelorussian and German breast cancer patients selected for familial disease (set 1, n = 63) or for the presence of the rs1800067 risk haplotype (set 2, n = 38). This study confirmed six known and one novel exonic variants, including four missense substitutions but no truncating mutation. Missense substitution p.R415Q (rs1800067), a previously postulated breast cancer susceptibility allele, was subsequently screened for in a total of 3,698 breast cancer cases and 2,868 controls from Germany, Belarus or Russia. The Gln415 allele appeared protective against breast cancer in the German series, with the strongest effect for ductal histology (OR 0.67; 95%CI 0.49; 0.92; p = 0.003), but this association was not confirmed in the other two series, with the combined analysis yielding an overall Mantel-Haenszel OR of 0.94 (95% CI 0.81; 1.08). There was no significant effect of p.R415Q on breast cancer survival in the German patient series. The other three detected ERCC4 missense mutations included two known rare variants as well as a novel substitution, p.E17V, that we identified on a p.R415Q haplotype background. The p.E17V mutation is predicted to be probably damaging but was present in just one heterozygous patient. We conclude that the contribution of ERCC4/FANCQ coding mutations to hereditary breast cancer in Central and Eastern Europe is likely to be small.
Published: 2014
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5. Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2.

Author: Tomas Kirchhoff, Mia M Gaudet, Antonis C Antoniou, Lesley McGuffog, Manjeet K Humphreys, Alison M Dunning, Stig E Bojesen, Børge G Nordestgaard, Henrik Flyger, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Sei-Hyun Ahn, Thilo Dork, Peter Schürmann, Johann H Karstens, Peter Hillemanns, Fergus J Couch, Janet Olson, Celine Vachon, Xianshu Wang, Angela Cox, Ian Brock, Graeme Elliott, Malcolm W R Reed, Barbara Burwinkel, Alfons Meindl, Hiltrud Brauch, Ute Hamann, Yon-Dschun Ko, GENICA Network, Annegien Broeks, Marjanka K Schmidt, Laura J Van 't Veer, Linde M Braaf, Nichola Johnson, Olivia Fletcher, Lorna Gibson, Julian Peto, Clare Turnbull, Sheila Seal, Anthony Renwick, Nazneen Rahman, Pei-Ei Wu, Jyh-Cherng Yu, Chia-Ni Hsiung, Chen-Yang Shen, Melissa C Southey, John L Hopper, Fleur Hammet, Thijs Van Dorpe, Anne-Sophie Dieudonne, Sigrid Hatse, Diether Lambrechts, Irene L Andrulis, Natalia Bogdanova, Natalia Antonenkova, Juri I Rogov, Daria Prokofieva, Marina Bermisheva, Elza Khusnutdinova, Christi J van Asperen, Robert A E M Tollenaar, Maartje J Hooning, Peter Devilee, Sara Margolin, Annika Lindblom, Roger L Milne, José Ignacio Arias, M Pilar Zamora, Javier Benítez, Gianluca Severi, Laura Baglietto, Graham G Giles, kConFab, AOCS Study Group, Amanda B Spurdle, Jonathan Beesley, Xiaoqing Chen, Helene Holland, Sue Healey, Shan Wang-Gohrke, Jenny Chang-Claude, Arto Mannermaa, Veli-Matti Kosma, Jaana Kauppinen, Vesa Kataja, Bjarni A Agnarsson, Maria A Caligo, Andrew K Godwin, Heli Nevanlinna, Tuomas Heikkinen, Zachary Fredericksen, Noralane Lindor, Katherine L Nathanson, Susan M Domchek, SWE-BRCA, Niklas Loman, Per Karlsson, Marie Stenmark Askmalm, Beatrice Melin, Anna von Wachenfeldt, HEBON, Frans B L Hogervorst, Martijn Verheus, Matti A Rookus, Caroline Seynaeve, Rogier A Oldenburg, Marjolijn J Ligtenberg, Margreet G E M Ausems, Cora M Aalfs, Hans J P Gille, Juul T Wijnen, Encarna B Gómez García, EMBRACE, Susan Peock, Margaret Cook, Clare T Oliver, Debra Frost, Craig Luccarini, Gabriella Pichert, Rosemarie Davidson, Carol Chu, Diana Eccles, Kai-Ren Ong, Jackie Cook, Fiona Douglas, Shirley Hodgson, D Gareth Evans, Rosalind Eeles, Bert Gold, Paul D P Pharoah, Kenneth Offit, Georgia Chenevix-Trench, Douglas F Easton, and BCAC/CIMBA
Subjects: Medicine, Science
Abstract: Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p =
Published: 2012
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6. Functional polymorphisms in the TERT promoter are associated with risk of serous epithelial ovarian and breast cancers.

Author: Jonathan Beesley, Hilda A Pickett, Sharon E Johnatty, Alison M Dunning, Xiaoqing Chen, Jun Li, Kyriaki Michailidou, Yi Lu, David N Rider, Rachel T Palmieri, Michael D Stutz, Diether Lambrechts, Evelyn Despierre, Sandrina Lambrechts, Ignace Vergote, Jenny Chang-Claude, Stefan Nickels, Alina Vrieling, Dieter Flesch-Janys, Shan Wang-Gohrke, Ursula Eilber, Natalia Bogdanova, Natalia Antonenkova, Ingo B Runnebaum, Thilo Dörk, Marc T Goodman, Galina Lurie, Lynne R Wilkens, Rayna K Matsuno, Lambertus A Kiemeney, Katja K H Aben, Tamara Marees, Leon F A G Massuger, Brooke L Fridley, Robert A Vierkant, Elisa V Bandera, Sara H Olson, Irene Orlow, Lorna Rodriguez-Rodriguez, Linda S Cook, Nhu D Le, Angela Brooks-Wilson, Linda E Kelemen, Ian Campbell, Simon A Gayther, Susan J Ramus, Aleksandra Gentry-Maharaj, Usha Menon, Shahana Ahmed, Caroline Baynes, Paul D Pharoah, kConFab Investigators, Australian Ovarian Cancer Study Group, ABCTB Investigators, Kenneth Muir, Artitaya Lophatananon, Arkom Chaiwerawattana, Surapon Wiangnon, Stuart Macgregor, Douglas F Easton, Roger R Reddel, Ellen L Goode, Georgia Chenevix-Trench, and Ovarian Cancer Association Consortium
Subjects: Medicine, Science
Abstract: Genetic variation at the TERT-CLPTM1L locus at 5p15.33 is associated with susceptibility to several cancers, including epithelial ovarian cancer (EOC). We have carried out fine-mapping of this region in EOC which implicates an association with a single nucleotide polymorphism (SNP) within the TERT promoter. We demonstrate that the minor alleles at rs2736109, and at an additional TERT promoter SNP, rs2736108, are associated with decreased breast cancer risk, and that the combination of both SNPs substantially reduces TERT promoter activity.
Published: 2011
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7. Polymorphisms in stromal genes and susceptibility to serous epithelial ovarian cancer: a report from the Ovarian Cancer Association Consortium.

Author: Ernest K Amankwah, Qinggang Wang, Joellen M Schildkraut, Ya-Yu Tsai, Susan J Ramus, Brooke L Fridley, Jonathan Beesley, Sharon E Johnatty, Penelope M Webb, Georgia Chenevix-Trench, Australian Ovarian Cancer Study Group, Laura C Dale, Diether Lambrechts, Frederic Amant, Evelyn Despierre, Ignace Vergote, Simon A Gayther, Aleksandra Gentry-Maharaj, Usha Menon, Jenny Chang-Claude, Shan Wang-Gohrke, Hoda Anton-Culver, Argyrios Ziogas, Thilo Dörk, Matthias Dürst, Natalia Antonenkova, Natalia Bogdanova, Robert Brown, James M Flanagan, Stanley B Kaye, James Paul, Ralf Bützow, Heli Nevanlinna, Ian Campbell, Diana M Eccles, Beth Y Karlan, Jenny Gross, Christine Walsh, Paul D P Pharoah, Honglin Song, Susanne Krüger Kjær, Estrid Høgdall, Claus Høgdall, Lene Lundvall, Lotte Nedergaard, Lambertus A L M Kiemeney, Leon F A G Massuger, Anne M van Altena, Sita H H M Vermeulen, Nhu D Le, Angela Brooks-Wilson, Linda S Cook, Catherine M Phelan, Julie M Cunningham, Celine M Vachon, Robert A Vierkant, Edwin S Iversen, Andrew Berchuck, Ellen L Goode, Thomas A Sellers, and Linda E Kelemen
Subjects: Medicine, Science
Abstract: Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among Caucasians were estimated with odds ratios (OR) among 397 cases and 920 controls in two U.S.-based studies (discovery set), 436 cases and 1,098 controls in Australia (replication set 1) and a consortium of 15 studies comprising 1,668 cases and 4,249 controls (replication set 2). The discovery set and replication set 1 (833 cases and 2,013 controls) showed statistically homogeneous (P(heterogeneity)≥0.48) decreased risks of sEOC at four variants: DCN rs3138165, rs13312816 and rs516115, and LUM rs17018765 (OR = 0.6 to 0.9; P(trend) = 0.001 to 0.03). Results from replication set 2 were statistically homogeneous (P(heterogeneity)≥0.13) and associated with increased risks at DCN rs3138165 and rs13312816, and LUM rs17018765: all ORs = 1.2; P(trend)≤0.02. The ORs at the four variants were statistically heterogeneous across all 18 studies (P(heterogeneity)≤0.03), which precluded combining. In post-hoc analyses, interactions were observed between each variant and recruitment period (P(interaction)≤0.003), age at diagnosis (P(interaction) = 0.04), and year of diagnosis (P(interaction) = 0.05) in the five studies with available information (1,044 cases, 2,469 controls). We conclude that variants in DCN and LUM are not directly associated with sEOC, and that confirmation of possible effect modification of the variants by non-genetic factors is required.
Published: 2011
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8. Data from Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

Author: Paul D.P. Pharoah, Simon A. Gayther, Matthew L. Freedman, Alvaro N.A. Monteiro, Thomas A. Sellers, Argyrios Ziogas, Wei Zheng, Hannah Yang, Anna Wu, Xifeng Wu, Yin-Ling Woo, Lynne R. Wilkens, Kristine G. Wicklund, Alice S. Whittemore, Nicolas Wentzensen, Christine Walsh, Shan Wang-Gohrke, Robert A. Vierkant, Ignace Vergote, Els Van Nieuwenhuysen, Anne M. van Altena, Shelley S. Tworoger, Ya-Yu Tsai, Agnieszka Timorek, Pamela J. Thompson, Kathryn L. Terry, Soo-Hwang Teo, Ingvild L. Tangen, Lara E. Sucheston-Campbell, Melissa C. Southey, Honglin Song, Weiva Sieh, Nadeem Siddiqui, Yurii B. Shvetsov, Xiao-Ou Shu, Ira Schwaab, Joellen M. Schildkraut, Helga B. Salvesen, Iwona K. Rzepecka, Ingo B. Runnebaum, Anja Rudolph, Joseph H. Rothstein, Mary Anne Rossing, Barry Rosen, Harvey A. Risch, Susan J. Ramus, Elizabeth M. Poole, Malcolm C. Pike, Catherine M. Phelan, Jennifer Permuth-Wey, Liisa M. Pelttari, Tanja Pejovic, Celeste Leigh Pearce, Rachel Palmieri Weber, Sandra Orsulic, Irene Orlow, Sara H. Olson, Kunle Odunsi, Heli Nevanlinna, Roberta B. Ness, Lotte Nedergaard, Steven A. Narod, Kirsten B. Moysich, Francesmary Modugno, Usha Menon, Iain A. McNeish, John R. McLaughlin, Valerie McGuire, Keitaro Matsuo, Leon Massuger, Lene Lundvall, Jan Lubinski, Karen Lu, Jolanta Lissowska, Dong Liang, Douglas A. Levine, Jenny Lester, Arto Leminen, Shashi Lele, Alice W. Lee, Nhu D. Le, Sandrina Lambrechts, Diether Lambrechts, Jolanta Kupryjanczyk, Camilla Krakstad, Lambertus A. Kiemeney, Joseph Kelley, Melissa Kellar, Linda E. Kelemen, Susanne K. Kjaer, Beth Y. Karlan, Bu-Tian Ji, Allan Jensen, James Paul, Anna Jakubowska, Edwin S. Iversen, Satoyo Hosono, Claus K. Hogdall, Estrid Hogdall, Peter Hillemanns, Michelle A.T. Hildebrandt, Florian Heitz, Alexander Hein, Philipp Harter, Patricia Harrington, Jacek Grownwald, Marc T. Goodman, Ellen L. Goode, Rosalind Glasspool, Graham G. Giles, Aleksandra Gentry-Maharaj, Yu-Tang Gao, Brooke L. Fridley, Peter A. Fasching, Arif B. Ekici, Robert P. Edwards, Douglas F. Easton, Diana Eccles, Matthias Dürst, Andreas du Bois, Thilo Dörk, Jennifer A. Doherty, Ed Dicks, Joe Dennis, Agnieszka Dansonka-Mieszkowska, Cezary Cybulski, Julie M. Cunningham, Daniel Cramer, Linda S. Cook, Zhihua Chen, Yian Ann Chen, Jenny Chang-Claude, Karen Carty, Ian Campbell, Ralf Butzow, Angela Brooks-Wilson, Louise Brinton, Natalia Bogdanova, Line Bjørge, Maria Bisogna, Andrew Berchuck, Matthias W. Beckmann, Yukie T. Bean, Elisa V. Bandera, Helen Baker, Georgia Chenevix-Trench, Natalia Antonenkova, Hoda Anton-Culver, Katja K.H. Aben, Kate Lawrenson, Qiyuan Li, Jonathan P. Tyrer, and Siddhartha P. Kar
Abstract: Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations.Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls).Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network.Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development.Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.
Published: 2023

9. Supplementary Table 2 from 9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium

Author: Isabel dos-Santos-Silva, Julian Peto, Qin Wang, Manjeet Humphreys, Douglas F. Easton, Minouk Schoemaker, Michael Jones, Anthony Swerdlow, Alan Ashworth, Maya Ghoussaini, Alison M. Dunning, Fiona M. Blows, Paul Pharoah, Malcolm W.R. Reed, Ian W. Brock, Simon S. Cross, Angela Cox, Jingmei Li, Jianjun Liu, Kamila Czene, Per Hall, Madeleine M.A. Tilanus-Linthorst, Agnes Jager, Antoinette Hollestelle, Maartje J. Hooning, Caroline M. Seynaeve, John W.M. Martens, Robert A.E.M. Tollenaar, Peter Devilee, Nayana Weerasooriya, Anna Marie Mulligan, Julia A. Knight, Irene L. Andrulis, Mervi Grip, Arja Jukkola-Vuorinen, Katri Pylkäs, Robert Winqvist, Alexander Miron, Esther M. John, Gianluca Severi, Cariona A. McLean, Laura Baglietto, Graham Giles, Janet Olson, Xianshu Wang, Celine Vachon, Fergus J. Couch, Paolo Radice, Siranoush Manoukian, Loris Bernard, Paolo Peterlongo, Sabine Behrens, Katharina Buck, Dieter Flesch-Janys, Caroline Weltens, Robert Paridaens, Ann Smeets, Diether Lambrechts, Xiaoqing Chen, Jonathan Beesley, Georgia Chenevix-Trench, Vesa Kataja, Jaana M. Hartikainen, Veli-Matti Kosma, Arto Mannermaa, Sara Margolin, Annika Lindblom, Elza Khusnutdinova, Guzel Zinnatullina, Darya Prokofyeva, Marina Bermisheva, Yuriy Rogov, Natalia Antonenkova, Natalia Bogdanova, Carl Blomqvist, Kristiina Aittomäki, Taru A. Muranen, Heli Nevanlinna, Peter Hillemanns, Michael Bremer, Peter Schürmann, Thilo Dörk, Ursula Eilber, Shan Wang-Gohrke, Jenny Chang-Claude, Thomas Brüning, Christina Justenhoven, Hiltrud Brauch, Rita K. Schmutzler, Claus R. Bartram, Michael Golatta, Alfons Meindl, Anne Langheinz, Volker Arndt, Heiko Müller, Hermann Brenner, Christina Clarke Dur, Leslie Bernstein, Argyrios Ziogas, Hoda Anton-Culver, M. Pilar Zamora, José-Ignacio Arias-Pérez, Javier Benítez, Roger L. Milne, Børge G Nordestgaard, Henrik Flyger, Sune F. Nielsen, Stig E Bojesen, Claire Mulot, Pierre Laurent-Puig, Thérèse Truong, Pascal Guénel, Christof Sohn, Andreas Schneeweiss, Frederik Marme, Barbara Burwinkel, Michael Kerin, Ian Tomlinson, Elinor J. Sawyer, Ruediger Schulz-Wendtland, Arif B. Ekici, Matthias W. Beckmann, Peter A. Fasching, Surapon Wiangnon, Arkom Chaiwerawattana, Artitaya Lophatananon, Kenneth R. Muir, Linda M. Braaf, Sten Cornelissen, Annegien Broeks, Marjanka K. Schmidt, Maryam Mahmoodi, Melissa C. Southey, Carmel Apicella, John L. Hopper, Nichola Johnson, Nick Orr, Olivia Fletcher, Frank Dudbridge, and Helen Warren
Abstract: PDF file, 70K, Availability of information on tumor morphology and receptor status for Europeans, by each included BCAC study.
Published: 2023

10. Supplementary Table Legend from 9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium

Author: Isabel dos-Santos-Silva, Julian Peto, Qin Wang, Manjeet Humphreys, Douglas F. Easton, Minouk Schoemaker, Michael Jones, Anthony Swerdlow, Alan Ashworth, Maya Ghoussaini, Alison M. Dunning, Fiona M. Blows, Paul Pharoah, Malcolm W.R. Reed, Ian W. Brock, Simon S. Cross, Angela Cox, Jingmei Li, Jianjun Liu, Kamila Czene, Per Hall, Madeleine M.A. Tilanus-Linthorst, Agnes Jager, Antoinette Hollestelle, Maartje J. Hooning, Caroline M. Seynaeve, John W.M. Martens, Robert A.E.M. Tollenaar, Peter Devilee, Nayana Weerasooriya, Anna Marie Mulligan, Julia A. Knight, Irene L. Andrulis, Mervi Grip, Arja Jukkola-Vuorinen, Katri Pylkäs, Robert Winqvist, Alexander Miron, Esther M. John, Gianluca Severi, Cariona A. McLean, Laura Baglietto, Graham Giles, Janet Olson, Xianshu Wang, Celine Vachon, Fergus J. Couch, Paolo Radice, Siranoush Manoukian, Loris Bernard, Paolo Peterlongo, Sabine Behrens, Katharina Buck, Dieter Flesch-Janys, Caroline Weltens, Robert Paridaens, Ann Smeets, Diether Lambrechts, Xiaoqing Chen, Jonathan Beesley, Georgia Chenevix-Trench, Vesa Kataja, Jaana M. Hartikainen, Veli-Matti Kosma, Arto Mannermaa, Sara Margolin, Annika Lindblom, Elza Khusnutdinova, Guzel Zinnatullina, Darya Prokofyeva, Marina Bermisheva, Yuriy Rogov, Natalia Antonenkova, Natalia Bogdanova, Carl Blomqvist, Kristiina Aittomäki, Taru A. Muranen, Heli Nevanlinna, Peter Hillemanns, Michael Bremer, Peter Schürmann, Thilo Dörk, Ursula Eilber, Shan Wang-Gohrke, Jenny Chang-Claude, Thomas Brüning, Christina Justenhoven, Hiltrud Brauch, Rita K. Schmutzler, Claus R. Bartram, Michael Golatta, Alfons Meindl, Anne Langheinz, Volker Arndt, Heiko Müller, Hermann Brenner, Christina Clarke Dur, Leslie Bernstein, Argyrios Ziogas, Hoda Anton-Culver, M. Pilar Zamora, José-Ignacio Arias-Pérez, Javier Benítez, Roger L. Milne, Børge G Nordestgaard, Henrik Flyger, Sune F. Nielsen, Stig E Bojesen, Claire Mulot, Pierre Laurent-Puig, Thérèse Truong, Pascal Guénel, Christof Sohn, Andreas Schneeweiss, Frederik Marme, Barbara Burwinkel, Michael Kerin, Ian Tomlinson, Elinor J. Sawyer, Ruediger Schulz-Wendtland, Arif B. Ekici, Matthias W. Beckmann, Peter A. Fasching, Surapon Wiangnon, Arkom Chaiwerawattana, Artitaya Lophatananon, Kenneth R. Muir, Linda M. Braaf, Sten Cornelissen, Annegien Broeks, Marjanka K. Schmidt, Maryam Mahmoodi, Melissa C. Southey, Carmel Apicella, John L. Hopper, Nichola Johnson, Nick Orr, Olivia Fletcher, Frank Dudbridge, and Helen Warren
Abstract: PDF file, 45K.
Published: 2023

11. Supplementary Table 3 from 9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium

Author: Isabel dos-Santos-Silva, Julian Peto, Qin Wang, Manjeet Humphreys, Douglas F. Easton, Minouk Schoemaker, Michael Jones, Anthony Swerdlow, Alan Ashworth, Maya Ghoussaini, Alison M. Dunning, Fiona M. Blows, Paul Pharoah, Malcolm W.R. Reed, Ian W. Brock, Simon S. Cross, Angela Cox, Jingmei Li, Jianjun Liu, Kamila Czene, Per Hall, Madeleine M.A. Tilanus-Linthorst, Agnes Jager, Antoinette Hollestelle, Maartje J. Hooning, Caroline M. Seynaeve, John W.M. Martens, Robert A.E.M. Tollenaar, Peter Devilee, Nayana Weerasooriya, Anna Marie Mulligan, Julia A. Knight, Irene L. Andrulis, Mervi Grip, Arja Jukkola-Vuorinen, Katri Pylkäs, Robert Winqvist, Alexander Miron, Esther M. John, Gianluca Severi, Cariona A. McLean, Laura Baglietto, Graham Giles, Janet Olson, Xianshu Wang, Celine Vachon, Fergus J. Couch, Paolo Radice, Siranoush Manoukian, Loris Bernard, Paolo Peterlongo, Sabine Behrens, Katharina Buck, Dieter Flesch-Janys, Caroline Weltens, Robert Paridaens, Ann Smeets, Diether Lambrechts, Xiaoqing Chen, Jonathan Beesley, Georgia Chenevix-Trench, Vesa Kataja, Jaana M. Hartikainen, Veli-Matti Kosma, Arto Mannermaa, Sara Margolin, Annika Lindblom, Elza Khusnutdinova, Guzel Zinnatullina, Darya Prokofyeva, Marina Bermisheva, Yuriy Rogov, Natalia Antonenkova, Natalia Bogdanova, Carl Blomqvist, Kristiina Aittomäki, Taru A. Muranen, Heli Nevanlinna, Peter Hillemanns, Michael Bremer, Peter Schürmann, Thilo Dörk, Ursula Eilber, Shan Wang-Gohrke, Jenny Chang-Claude, Thomas Brüning, Christina Justenhoven, Hiltrud Brauch, Rita K. Schmutzler, Claus R. Bartram, Michael Golatta, Alfons Meindl, Anne Langheinz, Volker Arndt, Heiko Müller, Hermann Brenner, Christina Clarke Dur, Leslie Bernstein, Argyrios Ziogas, Hoda Anton-Culver, M. Pilar Zamora, José-Ignacio Arias-Pérez, Javier Benítez, Roger L. Milne, Børge G Nordestgaard, Henrik Flyger, Sune F. Nielsen, Stig E Bojesen, Claire Mulot, Pierre Laurent-Puig, Thérèse Truong, Pascal Guénel, Christof Sohn, Andreas Schneeweiss, Frederik Marme, Barbara Burwinkel, Michael Kerin, Ian Tomlinson, Elinor J. Sawyer, Ruediger Schulz-Wendtland, Arif B. Ekici, Matthias W. Beckmann, Peter A. Fasching, Surapon Wiangnon, Arkom Chaiwerawattana, Artitaya Lophatananon, Kenneth R. Muir, Linda M. Braaf, Sten Cornelissen, Annegien Broeks, Marjanka K. Schmidt, Maryam Mahmoodi, Melissa C. Southey, Carmel Apicella, John L. Hopper, Nichola Johnson, Nick Orr, Olivia Fletcher, Frank Dudbridge, and Helen Warren
Abstract: PDF file, 57K, Genotyping characteristics of each BCAC participating study.
Published: 2023

12. Data from 9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium

Author: Isabel dos-Santos-Silva, Julian Peto, Qin Wang, Manjeet Humphreys, Douglas F. Easton, Minouk Schoemaker, Michael Jones, Anthony Swerdlow, Alan Ashworth, Maya Ghoussaini, Alison M. Dunning, Fiona M. Blows, Paul Pharoah, Malcolm W.R. Reed, Ian W. Brock, Simon S. Cross, Angela Cox, Jingmei Li, Jianjun Liu, Kamila Czene, Per Hall, Madeleine M.A. Tilanus-Linthorst, Agnes Jager, Antoinette Hollestelle, Maartje J. Hooning, Caroline M. Seynaeve, John W.M. Martens, Robert A.E.M. Tollenaar, Peter Devilee, Nayana Weerasooriya, Anna Marie Mulligan, Julia A. Knight, Irene L. Andrulis, Mervi Grip, Arja Jukkola-Vuorinen, Katri Pylkäs, Robert Winqvist, Alexander Miron, Esther M. John, Gianluca Severi, Cariona A. McLean, Laura Baglietto, Graham Giles, Janet Olson, Xianshu Wang, Celine Vachon, Fergus J. Couch, Paolo Radice, Siranoush Manoukian, Loris Bernard, Paolo Peterlongo, Sabine Behrens, Katharina Buck, Dieter Flesch-Janys, Caroline Weltens, Robert Paridaens, Ann Smeets, Diether Lambrechts, Xiaoqing Chen, Jonathan Beesley, Georgia Chenevix-Trench, Vesa Kataja, Jaana M. Hartikainen, Veli-Matti Kosma, Arto Mannermaa, Sara Margolin, Annika Lindblom, Elza Khusnutdinova, Guzel Zinnatullina, Darya Prokofyeva, Marina Bermisheva, Yuriy Rogov, Natalia Antonenkova, Natalia Bogdanova, Carl Blomqvist, Kristiina Aittomäki, Taru A. Muranen, Heli Nevanlinna, Peter Hillemanns, Michael Bremer, Peter Schürmann, Thilo Dörk, Ursula Eilber, Shan Wang-Gohrke, Jenny Chang-Claude, Thomas Brüning, Christina Justenhoven, Hiltrud Brauch, Rita K. Schmutzler, Claus R. Bartram, Michael Golatta, Alfons Meindl, Anne Langheinz, Volker Arndt, Heiko Müller, Hermann Brenner, Christina Clarke Dur, Leslie Bernstein, Argyrios Ziogas, Hoda Anton-Culver, M. Pilar Zamora, José-Ignacio Arias-Pérez, Javier Benítez, Roger L. Milne, Børge G Nordestgaard, Henrik Flyger, Sune F. Nielsen, Stig E Bojesen, Claire Mulot, Pierre Laurent-Puig, Thérèse Truong, Pascal Guénel, Christof Sohn, Andreas Schneeweiss, Frederik Marme, Barbara Burwinkel, Michael Kerin, Ian Tomlinson, Elinor J. Sawyer, Ruediger Schulz-Wendtland, Arif B. Ekici, Matthias W. Beckmann, Peter A. Fasching, Surapon Wiangnon, Arkom Chaiwerawattana, Artitaya Lophatananon, Kenneth R. Muir, Linda M. Braaf, Sten Cornelissen, Annegien Broeks, Marjanka K. Schmidt, Maryam Mahmoodi, Melissa C. Southey, Carmel Apicella, John L. Hopper, Nichola Johnson, Nick Orr, Olivia Fletcher, Frank Dudbridge, and Helen Warren
Abstract: Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).Methods: To further investigate the rs865686–breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case–control studies (48,394 cases, 50,836 controls).Results: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10−29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10−143], but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor–positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86–0.91; P = 3.13 × 10−22) but less strongly, if at all, with ER-negative (ER−) disease (OR, 0.98; 95% CI, 0.94–1.02; P = 0.26; Phet = 1.16 × 10−6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors.Conclusions: This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer.Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype. Cancer Epidemiol Biomarkers Prev; 21(10); 1783–. ©2012 AACR.
Published: 2023

13. Supplementary Tables S1-6, Figures S1-2 from Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

Author: Paul D.P. Pharoah, Simon A. Gayther, Matthew L. Freedman, Alvaro N.A. Monteiro, Thomas A. Sellers, Argyrios Ziogas, Wei Zheng, Hannah Yang, Anna Wu, Xifeng Wu, Yin-Ling Woo, Lynne R. Wilkens, Kristine G. Wicklund, Alice S. Whittemore, Nicolas Wentzensen, Christine Walsh, Shan Wang-Gohrke, Robert A. Vierkant, Ignace Vergote, Els Van Nieuwenhuysen, Anne M. van Altena, Shelley S. Tworoger, Ya-Yu Tsai, Agnieszka Timorek, Pamela J. Thompson, Kathryn L. Terry, Soo-Hwang Teo, Ingvild L. Tangen, Lara E. Sucheston-Campbell, Melissa C. Southey, Honglin Song, Weiva Sieh, Nadeem Siddiqui, Yurii B. Shvetsov, Xiao-Ou Shu, Ira Schwaab, Joellen M. Schildkraut, Helga B. Salvesen, Iwona K. Rzepecka, Ingo B. Runnebaum, Anja Rudolph, Joseph H. Rothstein, Mary Anne Rossing, Barry Rosen, Harvey A. Risch, Susan J. Ramus, Elizabeth M. Poole, Malcolm C. Pike, Catherine M. Phelan, Jennifer Permuth-Wey, Liisa M. Pelttari, Tanja Pejovic, Celeste Leigh Pearce, Rachel Palmieri Weber, Sandra Orsulic, Irene Orlow, Sara H. Olson, Kunle Odunsi, Heli Nevanlinna, Roberta B. Ness, Lotte Nedergaard, Steven A. Narod, Kirsten B. Moysich, Francesmary Modugno, Usha Menon, Iain A. McNeish, John R. McLaughlin, Valerie McGuire, Keitaro Matsuo, Leon Massuger, Lene Lundvall, Jan Lubinski, Karen Lu, Jolanta Lissowska, Dong Liang, Douglas A. Levine, Jenny Lester, Arto Leminen, Shashi Lele, Alice W. Lee, Nhu D. Le, Sandrina Lambrechts, Diether Lambrechts, Jolanta Kupryjanczyk, Camilla Krakstad, Lambertus A. Kiemeney, Joseph Kelley, Melissa Kellar, Linda E. Kelemen, Susanne K. Kjaer, Beth Y. Karlan, Bu-Tian Ji, Allan Jensen, James Paul, Anna Jakubowska, Edwin S. Iversen, Satoyo Hosono, Claus K. Hogdall, Estrid Hogdall, Peter Hillemanns, Michelle A.T. Hildebrandt, Florian Heitz, Alexander Hein, Philipp Harter, Patricia Harrington, Jacek Grownwald, Marc T. Goodman, Ellen L. Goode, Rosalind Glasspool, Graham G. Giles, Aleksandra Gentry-Maharaj, Yu-Tang Gao, Brooke L. Fridley, Peter A. Fasching, Arif B. Ekici, Robert P. Edwards, Douglas F. Easton, Diana Eccles, Matthias Dürst, Andreas du Bois, Thilo Dörk, Jennifer A. Doherty, Ed Dicks, Joe Dennis, Agnieszka Dansonka-Mieszkowska, Cezary Cybulski, Julie M. Cunningham, Daniel Cramer, Linda S. Cook, Zhihua Chen, Yian Ann Chen, Jenny Chang-Claude, Karen Carty, Ian Campbell, Ralf Butzow, Angela Brooks-Wilson, Louise Brinton, Natalia Bogdanova, Line Bjørge, Maria Bisogna, Andrew Berchuck, Matthias W. Beckmann, Yukie T. Bean, Elisa V. Bandera, Helen Baker, Georgia Chenevix-Trench, Natalia Antonenkova, Hoda Anton-Culver, Katja K.H. Aben, Kate Lawrenson, Qiyuan Li, Jonathan P. Tyrer, and Siddhartha P. Kar
Abstract: Supplementary Tables S1-6, Figures S1-2. Supplementary Table S1: Summary of serous EOC GWAS data sets; Supplementary Table S2: Genes in the six significant co-expression networks; Supplementary Table S3: GSEA results after LD-based clumping of SNPs; Supplementary Table S4: GSEA results for the replication data set (COGS); Supplementary Table S5: GSEA results for all networks with > 10 genes; Supplementary Table S6: Number of intragenic SNPs and genes covered by SNPs in the different analyses; Supplementary Figure S1: Q-Q plots of the minimum P-value among all SNPs in each gene with and without the modified Sidak correction; Supplementary Figure S2: Disease Association Protein-Protein Link Evaluator (DAPPLE) protein-protein interaction network
Published: 2023

14. Supplementary Table 1 from 9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium

Author: Isabel dos-Santos-Silva, Julian Peto, Qin Wang, Manjeet Humphreys, Douglas F. Easton, Minouk Schoemaker, Michael Jones, Anthony Swerdlow, Alan Ashworth, Maya Ghoussaini, Alison M. Dunning, Fiona M. Blows, Paul Pharoah, Malcolm W.R. Reed, Ian W. Brock, Simon S. Cross, Angela Cox, Jingmei Li, Jianjun Liu, Kamila Czene, Per Hall, Madeleine M.A. Tilanus-Linthorst, Agnes Jager, Antoinette Hollestelle, Maartje J. Hooning, Caroline M. Seynaeve, John W.M. Martens, Robert A.E.M. Tollenaar, Peter Devilee, Nayana Weerasooriya, Anna Marie Mulligan, Julia A. Knight, Irene L. Andrulis, Mervi Grip, Arja Jukkola-Vuorinen, Katri Pylkäs, Robert Winqvist, Alexander Miron, Esther M. John, Gianluca Severi, Cariona A. McLean, Laura Baglietto, Graham Giles, Janet Olson, Xianshu Wang, Celine Vachon, Fergus J. Couch, Paolo Radice, Siranoush Manoukian, Loris Bernard, Paolo Peterlongo, Sabine Behrens, Katharina Buck, Dieter Flesch-Janys, Caroline Weltens, Robert Paridaens, Ann Smeets, Diether Lambrechts, Xiaoqing Chen, Jonathan Beesley, Georgia Chenevix-Trench, Vesa Kataja, Jaana M. Hartikainen, Veli-Matti Kosma, Arto Mannermaa, Sara Margolin, Annika Lindblom, Elza Khusnutdinova, Guzel Zinnatullina, Darya Prokofyeva, Marina Bermisheva, Yuriy Rogov, Natalia Antonenkova, Natalia Bogdanova, Carl Blomqvist, Kristiina Aittomäki, Taru A. Muranen, Heli Nevanlinna, Peter Hillemanns, Michael Bremer, Peter Schürmann, Thilo Dörk, Ursula Eilber, Shan Wang-Gohrke, Jenny Chang-Claude, Thomas Brüning, Christina Justenhoven, Hiltrud Brauch, Rita K. Schmutzler, Claus R. Bartram, Michael Golatta, Alfons Meindl, Anne Langheinz, Volker Arndt, Heiko Müller, Hermann Brenner, Christina Clarke Dur, Leslie Bernstein, Argyrios Ziogas, Hoda Anton-Culver, M. Pilar Zamora, José-Ignacio Arias-Pérez, Javier Benítez, Roger L. Milne, Børge G Nordestgaard, Henrik Flyger, Sune F. Nielsen, Stig E Bojesen, Claire Mulot, Pierre Laurent-Puig, Thérèse Truong, Pascal Guénel, Christof Sohn, Andreas Schneeweiss, Frederik Marme, Barbara Burwinkel, Michael Kerin, Ian Tomlinson, Elinor J. Sawyer, Ruediger Schulz-Wendtland, Arif B. Ekici, Matthias W. Beckmann, Peter A. Fasching, Surapon Wiangnon, Arkom Chaiwerawattana, Artitaya Lophatananon, Kenneth R. Muir, Linda M. Braaf, Sten Cornelissen, Annegien Broeks, Marjanka K. Schmidt, Maryam Mahmoodi, Melissa C. Southey, Carmel Apicella, John L. Hopper, Nichola Johnson, Nick Orr, Olivia Fletcher, Frank Dudbridge, and Helen Warren
Abstract: PDF file, 107K, Summary characteristics of the participating BCAC case-control studies.
Published: 2023

15. Polygenic Risk Modelling for Prediction of Epithelial Ovarian Cancer Risk

Author: V. Wendy Setiawan, Ana Osorio, Liv Cecilie Vestrheim Thomsen, Francesca Gensini, Harsha Pathak, Barbara Wappenschmidt, Ingo B. Runnebaum, Javier Benitez, Rita K. Schmutzler, Jeffrey N. Weitzel, Yin Ling Woo, Kenneth Offit, Anthony N. Karnezis, Eitan Friedman, Jacques Simard, James M. Flanagan, Pedro Pérez-Segura, Siranoush Manoukian, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Graham G. Giles, Usha Menon, Ava Kwong, Anna H. Wu, Thomas Hansen, Cristina Rodríguez-Antona, Maria A. Caligo, Argyrios Ziogas, Allison DePersia, Anna P. Sokolenko, Clarice R. Weinberg, Hoda Anton-Culver, Digna R. Velez Edwards, Jennifer B. Permuth, Patricia A. Ganz, Ana Vega, Keitaro Matsuo, Heli Nevanlinna, Frances Wang, Natalia Antonenkova, Claudine Isaacs, Conxi Lázaro, Melissa C. Larson, Henriette Roed Nielsen, Byoung-Gie Kim, Andreas du Bois, Dale P. Sandler, Anna Jakubowska, Paul D.P. Pharoah, Jenny Lester, Paolo Radice, Natalia Bogdanova, Lambertus A. Kiemeney, Mary Anne Rossing, Thilo Dörk, Ruea-Yea Huang, Judy Garber, Taymaa May, Diana Eccles, Mary Beth Terry, Jenny Chang-Claude, Jeffrey R. Marks, Dominique Stoppa-Lyonnet, Heather Eliassen, Douglas A. Levine, Phuong L. Mai, Gerasimos Aravantinos, Hui Cai, Britton Trabert, Amanda Black, Noura Mebirouk, Robin de Putter, Rayna K. Matsuno, Ralf Bützow, Joanne Ngeow Yuen Yie, James D. Brenton, Nadine Tung, Drakoulis Yannoukakos, Jonathan Tyrer, L Yan, Yen Y. Tan, Ian Komenaka, Simona Agata, Honglin Song, Tanja Pejovic, Marjorie J. Riggan, Antonis C. Antoniou, Katja K.H. Aben, Goska Leslie, Eric A. Ross, Estrid Høgdall, Kang Shan, Holly R. Harris, Eleanor Davies, Liene Nikitina-Zake, Florian Heitz, Stephen J. Chanock, Matthew Jones, Beth Y. Karlan, Matthias W. Beckmann, Penelope M. Webb, John L. Hopper, Peter A. Fasching, Jacek Gronwald, kConFab Investigators, Ana Peixoto, Joellen M. Schildkraut, Renée T. Fortner, Susan L. Neuhausen, Daehee Kang, Anthony J. Swerdlow, Lesley McGuffog, Marco Montagna, Paolo Peterlongo, Daniel R. Barnes, Marina Bermisheva, Alicja Wolk, Yuan Chun Ding, Marc Tischkowitz, Gord Glendon, Elza Khusnutdinova, Julie M. Cunningham, Saundra S. Buys, Albina N. Minlikeeva, Jennifer A. Doherty, Annemieke H. van der Hout, Austin Miller, Fergus J. Couch, Fabienne Lesueur, Peter Devilee, Kristin K. Zorn, Daniel Barrowdale, Christian F. Singer, Line Bjørge, Åke Borg, Diether Lambrechts, Shelley S. Tworoger, Allan Jensen, Ute Hamann, Douglas F. Easton, Bernardo Bonanni, Alvaro N.A. Monteiro, Johanna Rantala, Marc T. Goodman, Ellen Valen, Wei Zheng, Thomas A. Sellers, Marcus Q. Bernardini, Alice S. Whittemore, Kunle Odunsi, Inge Søkilde Pedersen, Laura Papi, Mads Thomassen, Allison W. Kurian, Emily White, Penny Soucy, D. Gareth Evans, Lenka Foretova, Kathryn L. Terry, Ruth C. Travis, Claus Høgdall, Hebon Investigators, Darya Prokofyeva, Stacey J. Winham, Yoke-Eng Chiew, Eileen Dareng, Jan Lubinski, Elizabeth Munro, Oskar T. Johannsson, Linda E. Kelemen, Kexin Chen, Xin Yang, Manuel R. Teixeira, Anna M. Piskorz, Edith Olah, Helen Steed, Beth N. Peshkin, Georgia Chenevix-Trench, Andrew K. Godwin, Pamela J. Thompson, Chad D. Huff, Rosa B. Barkardottir, Muriel A. Adank, Mikael Hartman, Linda J. Titus, Weiva Sieh, Simon A. Gayther, Peter J. Hulick, Michael T. Parsons, Elisa V. Bandera, Amanda E. Toland, Miguel de la Hoya, Orland Diez, Alicia Beeghly-Fadiel, Rebecca Sutphen, Francesmary Modugno, Judith Balmaña, Christoph Engel, Harvey A. Risch, Elizabeth J. van Rensburg, Michael Jones, Rikki Cannioto, Michelle A.T. Hildebrandt, Soo Hwang Teo, Fanny Dao, Susan J. Ramus, Sarah Colanna, Kathleen Claes, David G. Huntsman, Siel Olbrecht, Esther M. John, Robert A. Vierkant, Wendy K. Chung, Ellen L. Goode, Olufunmilayo I. Olopade, Evgeny N. Imyanitov, Joe Dennis, Andrew Berchuck, Banu Arun, Darcy L. Thull, Lian Li, Celeste Leigh Pearce, Sue K. Park, Susan M. Domchek, Agnieszka Budzilowska, Håkan Olsson, Susanne K. Kjaer, Mark H. Greene, Katia M. Zavaglia, Jolanta Kupryjanczyk, Nicolas Wentzensen, Karen H. Lu, Hayley Cassingham, Christopher A. Haiman, Eric Hahnen, Els Van Nieuwenhuysen, Katherine L. Nathanson, Anna deFazio, Ian G. Campbell, Paul A. James, Sara H. Olson, Eva Machackova, Anne M. van Altena, Irene L. Andrulis, Linda S. Cook, Matthias Dürst, Mary B. Daly, John R. McLaughlin, Niclas Håkansson, Jingmei Li, Diana Torres, Iain A. McNeish, Jennifer T. Loud, Roger L. Milne, Marta Santamariña, Annelie Augustinsson, Nhu D. Le, Kate Lawrenson, Kirsten B. Moysich, Dareng, Eileen O [0000-0003-0802-419X], Tyrer, Jonathan [0000-0003-3724-4757], Barnes, Daniel [0000-0002-3781-7570], Jones, Michelle R [0000-0001-5466-3844], Agata, Simona [0000-0002-6329-0768], Anton-Culver, Hoda [0000-0002-9603-0110], Augustinsson, Annelie [0000-0003-3415-0536], Bandera, Elisa V [0000-0002-8789-2755], Barkardottir, Rosa B [0000-0003-0629-2772], Brenton, James [0000-0002-5738-6683], Campbell, Ian [0000-0002-7773-4155], Chen, Kexin [0000-0003-1010-8093], Chung, Wendy K [0000-0003-3438-5685], Claes, Kathleen BM [0000-0003-0841-7372], Devilee, Peter [0000-0002-8023-2009], Diez, Orland [0000-0001-7339-0570], Bois, Andreas du [0000-0002-8477-506X], Eccles, Diana M [0000-0002-9935-3169], Eliassen, Heather A [0000-0002-3961-6609], Ganz, Patricia A [0000-0002-1841-4143], Giles, Graham G [0000-0003-4946-9099], Glendon, Gord [0000-0001-8630-6673], Greene, Mark H [0000-0003-1852-9239], Hartman, Mikael [0000-0001-5726-9965], Heitz, Florian [0000-0002-2412-0352], Isaacs, Claudine [0000-0002-9646-1260], Janavicius, Ramunas [0000-0002-3773-8485], John, Esther M [0000-0003-3259-8003], Kang, Daehee [0000-0003-4031-5878], Karlan, Beth Y [0000-0002-9451-2933], Khusnutdinova, Elza [0000-0003-2987-3334], Kjaer, Susanne K [0000-0002-8347-1398], Manoukian, Siranoush [0000-0002-6034-7562], Matsuo, Keitaro [0000-0003-1761-6314], Menon, Usha [0000-0003-3708-1732], Miller, Austin [0000-0001-9739-8462], Nikitina-Zake, Liene [0000-0003-2491-5187], Olbrecht, Siel [0000-0001-9452-5905], Olopade, Olufunmilayo I [0000-0002-9936-1599], Olson, Sara H [0000-0003-0182-2754], Papi, Laura [0000-0003-4552-9517], Park, Sue K [0000-0001-5002-9707], Parsons, Michael T [0000-0003-3242-8477], Permuth, Jennifer B [0000-0002-4726-9264], Peterlongo, Paolo [0000-0001-6951-6855], Radice, Paolo [0000-0001-6298-4111], Swerdlow, Anthony J [0000-0001-5550-4159], Toland, Amanda E [0000-0002-0271-1792], Webb, Penelope M [0000-0003-0733-5930], Weinberg, Clarice R [0000-0002-7713-8556], Weitzel, Jeffrey N [0000-0001-6714-092X], Winham, Stacey J [0000-0002-8492-9102], Wolk, Alicja [0000-0001-7387-6845], Yannoukakos, Drakoulis [0000-0001-7509-3510], Easton, Douglas [0000-0003-2444-3247], Ramus, Susan J [0000-0003-0005-7798], Chenevix-Trench, Georgia [0000-0002-1878-2587], and Apollo - University of Cambridge Repository
Subjects: Oncology, medicine.medical_specialty, 45/61, 45/43, Single-nucleotide polymorphism, Logistic regression, 631/208/2489, 03 medical and health sciences, 0302 clinical medicine, Lasso (statistics), Internal medicine, Genotype, medicine, SNP, 030304 developmental biology, 0303 health sciences, business.industry, Hazard ratio, article, Odds ratio, 631/208/721, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, business, Ovarian cancer, 692/499
Abstract: Funder: Funding details are provided in the Supplementary Material, Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, ��select and shrink for summary statistics�� (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28��1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08��1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30��1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022
Full Text: View/download PDF

16. Publisher Correction: Shared heritability and functional enrichment across six solid cancers

Author: Karina Dalsgaard Sørensen, Mattias Johansson, Manjeet K. Bolla, Kay-Tee Khaw, Carl Blomqvist, Joan Brunet, Robert L. Ferris, Graham G. Giles, Ruth C. Travis, Philip Lazarus, Stephan Lam, Stella Koutros, Michael Hoffmeister, Liene Nikitina-Zake, Adonina Tardón, Christopher I. Amos, Emmanouil Saloustros, Christopher K. Edlund, Jacqueline M. Lane, Ana Osorio, Dijana Plaseska-Karanfilska, Catherine M. Tangen, Brenda Diergaarde, Mark C. Weissler, Diana Eccles, Per Hall, Mark H. Greene, Pascal Guénel, Amanda B. Spurdle, Marco Montagna, Sara Margolin, Gary E. Goodman, Irene L. Andrulis, Hongbing Shen, Barry S. Rosenstein, Hedy S. Rennert, Julie M. Cunningham, Paul Brennan, Jeroen R. Huyghe, Andrew T. Chan, Henrik Grönberg, Orland Diez, Hiltrud Brauch, Eunjung Lee, Trinidad Caldés, V. Wendy Setiawan, Matthias W. Beckmann, Angeline S. Andrew, Pooja Middha, Shelley S. Tworoger, Maria Teresa Landi, Alison M. Dunning, Jenny Lester, Angela Cox, Daniel R. Barnes, Jong Y. Park, Renée T. Fortner, Peter Kraft, Florentia Fostira, Mary Beth Terry, Jenny Chang-Claude, Tabea Kühl, Dale P. Sandler, Jeri Kim, Sue A. Ingles, Andy R Ness, Younghun Han, Marc Tischkowitz, Evgeny N. Imyanitov, Annika Lindblom, Ralf Bützow, Austin Miller, Kamila Czene, Jochen Hampe, Robert J. Hamilton, José A. García-Sáenz, Kenneth Muir, Wei Zheng, Gad Rennert, Johanna Schleutker, Mary Anne Rossing, Thilo Dörk, Andrew Berchuck, Angela Risch, Jyotsna Batra, Michael O. Woods, Julia A. Knight, Elinor J. Sawyer, Kim De Ruyck, Douglas F. Easton, Jeffrey N. Weitzel, Anna H. Wu, Børge G. Nordestgaard, Francesmary Modugno, Alkes L. Price, Douglas A. Levine, Lorelei A. Mucci, John L. Hopper, Davor Lessel, Javier Benitez, Richard S. Houlston, Diana Torres, Corina Lesseur, Arto Mannermaa, Daniel D. Buchanan, Mary B. Daly, Xifeng Wu, Matthew B. Schabath, Barbara Burwinkel, Bogdan Pasaniuc, Graham Casey, Peter A. Fasching, David G. Huntsman, Mads Thomassen, Manuela Gago-Dominguez, Lesley McGuffog, Christian F. Singer, Patricia A. Ganz, Manolis Kogevinas, Andrew F. Olshan, André Lopes Carvalho, Polly A. Newcomb, Banu Arun, Sonja I. Berndt, Niclas Håkansson, Leon Raskin, Marc T. Goodman, M. Dawn Teare, Hoda Anton-Culver, Fergus J. Couch, Christopher I. Li, Peter Devilee, Kristin K. Zorn, Neil E. Caporaso, Chu Chen, Kenneth Offit, Eitan Friedman, Natalia Antonenkova, Ute Hamann, Karin Sundfeldt, Stephanie A. Bien, Weiva Sieh, Rosalind A. Eeles, Claudine Isaacs, Maria A. Caligo, Nhu D. Le, Ulrike Peters, Triantafillos Liloglou, Stefania Boccia, Jacques Simard, Melissa C. Southey, Kathleen Claes, Darya Prokofyeva, Heike Bickeböller, Argyrios Ziogas, Sebastian Stintzing, Rayjean J. Hung, Carolina Ellberg, Rolando Herrero, Jennifer Stone, David C. Christiani, Mikael Johansson, Wilbert H.M. Peters, Montserrat Garcia-Closas, Jan Lubinski, Marcia Cruz Correa, Gabriella Cadoni, Rebecca Sutphen, Cornelia M. Ulrich, Paul A. Townsend, Qin Wang, Li Li, Nadine Tung, Ellen L. Goode, Silvia Franceschi, Lisa A. Cannon-Albright, Finn Cilius Nielsen, Stephanie L. Schmit, Antonis C. Antoniou, Clarice R. Weinberg, Kyriaki Michailidou, Susanne M. Arnold, Li Hsu, Natalia Bogdanova, Victor Moreno, Paolo Radice, Peter Hillemanns, Eloiza H. Tajara, Olufunmilayo I. Olopade, Stephen B. Gruber, Heli Nevanlinna, Kari Stefansson, Yun-Chul Hong, Amit Joshi, Emily White, Peter J. Hulick, Aage Haugen, Sara Benlloch, Mark A. Jenkins, Xia Jiang, Peter T. Campbell, Jack A. Taylor, Christopher A. Haiman, Jenny L Donovan, Roger L. Milne, Stephen J. Chanock, Judy Garber, Stig E. Bojesen, Taymaa May, David E. Neal, Kirsten B. Moysich, Jane C. Figueiredo, Alfons Meindl, Georgia Chenevix-Trench, Frank Claessens, Melinda C. Aldrich, Gregory Idos, Robert L. Nussbaum, Robert Winqvist, Tanja Pejovic, H-Erich Wichmann, Diether Lambrechts, Eric J. Duell, Demetrius Albanes, Drakoulis Yannoukakos, Kathryn L. Penney, Loic Le Marchand, Florian Heitz, Beth Y. Karlan, Lovise Maehle, Fotios Loupakis, Ana Vega, Zsofia Kote-Jarai, Marjorie J. Riggan, Stephen N. Thibodeau, Fredrik Wiklund, Steven Gallinger, Hans Brunnström, Geoffrey Liu, Duncan Thomas, Kathryn L. Terry, Els Van Nieuwenhuysen, Anthony J. Swerdlow, Miguel E. Aguado-Barrera, Nawaid Usmani, Mia M. Gaudet, David J. Hunter, Estrid Høgdall, Kristan J. Aronson, Vessela N. Kristensen, Line Bjørge, Amanda E. Toland, Anna Marie Mulligan, Noralane M. Lindor, Flavio Lejbkowicz, Jonathan Tyrer, James D. Brenton, Alice S. Whittemore, Catharine M L West, Goska Leslie, Jacek Gronwald, Martha L. Slattery, Christiane Maier, Radka Kaneva, Joe Dennis, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Erin M. Siegel, Paul A. James, Penella J. Woll, Catherine M. Phelan, Susan J. Ramus, Olivia Fletcher, Hermann Brenner, Geraldine Cancel-Tassin, Marjanka K. Schmidt, D. Gareth Evans, Manuel R. Teixeira, Amanda I. Phipps, Jolanta Kupryjanczyk, Penelope M. Webb, James McKay, Shanbeh Zienolddiny, Sara Lindström, Lambertus A. Kiemeney, Celine M. Vachon, Ali Amin Al Olama, Edith Olah, Andrew K. Godwin, Victoria L. Stevens, Mark N. Brook, Fredrick R. Schumacher, Digna R. Velez Edwards, Lisa F. Newcomb, Michael T. Parsons, David V. Conti, J. Margriet Collée, Rosa B. Barkardottir, Simon A. Gayther, Miranda Pring, Harvey A. Risch, Karoline Kuchenbaecker, Martin Lacko, Judith A. Clements, Mark S. Goldberg, Adam S. Kibel, Robert J. MacInnis, Richa Saxena, Heinz-Josef Lenz, Linda E. Kelemen, Stephanie J. Weinstein, Elisa V. Bandera, Freddie C. Hamdy, Håkan Olsson, Cezary Cybulski, Katherine L. Nathanson, Anna deFazio, Ian G. Campbell, Nora Pashayan, Hilary K. Finucane, Hardev Pandha, Susan L. Neuhausen, Alicja Wolk, Elizabeth J. van Rensburg, Esther M. John, Daniele Campa, Kjell Grankvist, Janet L. Stanford, Miriam Dwek, Susanne K. Kjaer, Monique J. Roobol, and Elza Khusnutdinova
Subjects: Genetics, 0303 health sciences, Multidisciplinary, business.industry, Published Erratum, Science, MEDLINE, General Physics and Astronomy, General Chemistry, Heritability, General Biochemistry, Genetics and Molecular Biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Medicine, lcsh:Q, lcsh:Science, business, solid cancers, 030304 developmental biology
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2019

17. Shared heritability and functional enrichment across six solid cancers

Author: Graham G. Giles, Diana Eccles, Cezary Cybulski, Catherine M. Tangen, Leon Raskin, Per Hall, Ana Vega, Hedy S. Rennert, Andrew T. Chan, Stephan Lam, Michael Hoffmeister, Angeline S. Andrew, Claudine Isaacs, Matthias W. Beckmann, Vessela N. Kristensen, Julia A. Knight, Mark S. Goldberg, Jonathan Tyrer, Jane C. Figueiredo, Katherine L. Nathanson, Anna deFazio, Ian G. Campbell, Nora Pashayan, Liene Nikitina-Zake, Goska Leslie, Rosalind A. Eeles, Line Bjørge, Adonina Tardón, Angela Cox, Gregory Idos, Evgeny N. Imyanitov, Manolis Kogevinas, Marc Tischkowitz, Hilary K. Finucane, Hardev Pandha, Rayjean J. Hung, Davor Lessel, Richard S. Houlston, Andrew F. Olshan, André Lopes Carvalho, James D. McKay, Kenneth Offit, Penelope M. Webb, Barry S. Rosenstein, Melinda C. Aldrich, Alice S. Whittemore, Austin Miller, Miguel E. Aguado-Barrera, Amanda E. Toland, Anna Marie Mulligan, Catharine M L West, Susan J. Ramus, Jennifer Stone, David C. Christiani, Clarice R. Weinberg, Olivia Fletcher, Kyriaki Michailidou, Demetrius Albanes, Chu Chen, Jenny L Donovan, Linda E. Kelemen, Carolina Ellberg, Hermann Brenner, Eitan Friedman, Sara Margolin, Jacek Gronwald, Argyrios Ziogas, Elisa V. Bandera, Qin Wang, Christopher I. Amos, Swe-Brca, Douglas F. Easton, Karin Sundfeldt, John L. Hopper, Jong Y. Park, Børge G. Nordestgaard, Johanna Schleutker, Freddie C. Hamdy, Alicja Wolk, Graham Casey, Radka Kaneva, Joe Dennis, Francesmary Modugno, Paolo Radice, Aage Haugen, Ralf Bützow, Barbara Burwinkel, Maria A. Caligo, Paul A. Townsend, Daniel D. Buchanan, Håkan Olsson, Li Li, Elza Khusnutdinova, Karina Dalsgaard Sørensen, Marco Montagna, Patricia A. Ganz, Kirsten B. Moysich, Stephen B. Gruber, Geraldine Cancel-Tassin, Mary Anne Rossing, Mads Thomassen, Manuela Gago-Dominguez, Marjanka K. Schmidt, Jolanta Kupryjanczyk, Melissa C. Southey, Finn Cilius Nielsen, Sara Benlloch, Roger L. Milne, Manuel R. Teixeira, Taymaa May, David V. Conti, Thilo Dörk, Kathleen Claes, Manjeet K. Bolla, Douglas A. Levine, Lorelei A. Mucci, Irene L. Andrulis, Carl Blomqvist, Sara Lindström, Marjorie J. Riggan, Ellen L. Goode, Jenny Lester, Jack A. Taylor, Adam S. Kibel, Jyotsna Batra, Stephen N. Thibodeau, Elinor J. Sawyer, Stefania Boccia, Jacques Simard, Robert J. MacInnis, Fredrik Wiklund, Geoffrey Liu, Robert Winqvist, Robert J. Hamilton, Joan Brunet, Olufunmilayo I. Olopade, Jeffrey N. Weitzel, Susan L. Neuhausen, Robert L. Ferris, Georgia Chenevix-Trench, Elizabeth J. van Rensburg, Amanda B. Spurdle, Jeroen R. Huyghe, Stig E. Bojesen, Eric J. Duell, Christopher A. Haiman, Bogdan Pasaniuc, Wilbert H.M. Peters, M. Dawn Teare, Marc T. Goodman, Richa Saxena, Renée T. Fortner, Shanbeh Zienolddiny, Mia M. Gaudet, Stephanie J. Weinstein, Mikael Johansson, Heli Nevanlinna, Nhu D. Le, Rolando Herrero, Peter Kraft, Steven Gallinger, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Erin M. Siegel, Gabriella Cadoni, Weiva Sieh, Esther M. John, Rebecca Sutphen, Kari Stefansson, Loic Le Marchand, David J. Hunter, Alkes L. Price, Judy Garber, Mary B. Daly, Flavio Lejbkowicz, Lambertus A. Kiemeney, Martha L. Slattery, Arto Mannermaa, Christian F. Singer, Daniele Campa, Hans Brunnström, Hongbing Shen, Els Van Nieuwenhuysen, V. Wendy Setiawan, Penella J. Woll, Catherine M. Phelan, Christopher I. Li, Robert L. Nussbaum, Niclas Håkansson, Triantafillos Liloglou, Stella Koutros, Kjell Grankvist, James D. Brenton, Annika Lindblom, Gad Rennert, Karoline Kuchenbaecker, Martin Lacko, Gary E. Goodman, Fredrick R. Schumacher, Henrik Grönberg, Diana Torres, J. Margriet Collée, Rosa B. Barkardottir, Amit Joshi, Trinidad Caldés, Mary Beth Terry, Jenny Chang-Claude, Paul Brennan, Simon A. Gayther, Mark H. Greene, Daniel R. Barnes, Janet L. Stanford, Miriam Dwek, Christiane Maier, Susanne K. Kjaer, Florentia Fostira, Miranda Pring, Noralane M. Lindor, Harvey A. Risch, David G. Huntsman, Kim De Ruyck, Judith A. Clements, Pooja Middha, Alison M. Dunning, Nadine Tung, Sebastian Stintzing, Michael O. Woods, Stephen J. Chanock, Andrew K. Godwin, Kenneth Muir, Eloiza H. Tajara, Silvia Franceschi, Xia Jiang, Li Hsu, Emily White, Peter T. Campbell, Paul A. James, Josef Heinz-Lenz, Ali Amin Al Olama, Victoria L. Stevens, Lovise Maehle, Fotios Loupakis, Peter Devilee, Orland Diez, Kristin K. Zorn, Stephanie A. Bien, Maria Teresa Landi, Mark A. Jenkins, Amanda I. Phipps, Alfons Meindl, Frank Claessens, Mark N. Brook, Kathryn L. Penney, Digna R. Velez Edwards, Montserrat Garcia-Closas, Diether Lambrechts, Zsofia Kote-Jarai, Fergus J. Couch, Duncan Thomas, Kathryn L. Terry, Ute Hamann, Heike Bickeböller, Christopher K. Edlund, Ana Osorio, Younghun Han, Jochen Hampe, Tee Kay-Khaw, Corina Lesseur, Peter A. Fasching, Lesley McGuffog, Eunjung Lee, Tabea Kühl, Andy R Ness, Kamila Czene, Angela Risch, Aocs Mod SQuaD, Jeri Kim, Anna H. Wu, Jacqueline M. Lane, Brenda Diergaarde, Ruth C. Travis, Julie M. Cunningham, Philip Lazarus, Shelley S. Tworoger, Natalia Antonenkova, Emmanouil Saloustros, Wei Zheng, Javier Benitez, Dijana Plaseska-Karanfilska, Mark C. Weissler, Marcia Cruz Correa, Hoda Anton-Culver, Neil E. Caporaso, Cornelia M. Ulrich, Stephanie L. Schmit, Antonis C. Antoniou, Victor Moreno, David E. Neal, Tanja Pejovic, Erich H-Wichmann, Pascal Guénel, Mattias Johansson, Florian Heitz, Beth Y. Karlan, Sonja I. Berndt, Anthony J. Swerdlow, Estrid Høgdall, Hiltrud Brauch, Ulrike Peters, D. Gareth Evans, Celine M. Vachon, Edith Olah, Dale P. Sandler, Lisa F. Newcomb, Michael T. Parsons, Lisa A. Cannon-Albright, Peter J. Hulick, José A. García-Sáenz, Sue A. Ingles, Andrew Berchuck, Peter Hillemanns, Matthew B. Schabath, Polly A. Newcomb, Banu Arun, Xifeng Wu, Darya Prokofyeva, Jan Lubinski, Susanne M. Arnold, Natalia Bogdanova, Drakoulis Yannoukakos, Nawaid Usmani, Kristan J. Aronson, Chul Yun-Hong, Monique J. Roobol, Clinical Genetics, Urology, Læknadeild (HÍ), Faculty of Medicine (UI), Lífvísindasetur (HÍ), Biomedical Center (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Finucane, Hilary K [0000-0003-3864-9828], Schumacher, Fredrick R [0000-0002-3073-7463], Schmit, Stephanie L [0000-0001-5931-1194], Michailidou, Kyriaki [0000-0001-7065-1237], Kuchenbaecker, Karoline B [0000-0001-9726-603X], Dennis, Joe [0000-0003-4591-1214], Huyghe, Jeroen R [0000-0001-6027-9806], Andrulis, Irene L [0000-0002-4226-6435], Arnold, Susanne M [0000-0001-6542-9551], Barnes, Daniel R [0000-0002-3781-7570], Batra, Jyotsna [0000-0003-4646-6247], Bojesen, Stig E [0000-0002-4061-4133], Brauch, Hiltrud [0000-0001-7531-2736], Brenton, James D [0000-0002-5738-6683], Brook, Mark N [0000-0002-8969-2378], Brunet, Joan [0000-0003-1945-3512], Brunnström, Hans [0000-0001-7402-138X], Buchanan, Daniel D [0000-0003-2225-6675], Campbell, Ian [0000-0002-7773-4155], Cancel-Tassin, Géraldine [0000-0002-9583-6382], Chan, Andrew T [0000-0001-7284-6767], Chanock, Stephen J [0000-0002-2324-3393], Claes, Kathleen BM [0000-0003-0841-7372], Cunningham, Julie M [0000-0002-8159-3025], Devilee, Peter [0000-0002-8023-2009], Ellberg, Carolina [0000-0001-7297-0645], Fasching, Peter A [0000-0003-4885-8471], Liloglou, Triantafillos [0000-0003-0460-1404], Fletcher, Olivia [0000-0001-9387-7116], García-Sáenz, José A [0000-0001-6880-0301], Grankvist, Kjell [0000-0003-4289-2097], Greene, Mark H [0000-0003-1852-9239], Gronberg, Henrik [0000-0002-1073-2753], Guénel, Pascal [0000-0002-8359-518X], Hampe, Jochen [0000-0002-2421-6127], Houlston, Richard [0000-0002-5268-0242], Hulick, Peter J [0000-0001-8397-4078], James, Paul [0000-0002-4361-4657], Jenkins, Mark A [0000-0002-8964-6160], Joshi, Amit D [0000-0001-7581-6934], Lambrechts, Diether [0000-0002-3429-302X], Leslie, Goska [0000-0001-5756-6222], Lessel, Davor [0000-0003-4496-244X], Levine, Douglas A [0000-0003-1038-8232], Miller, Austin [0000-0001-9739-8462], Milne, Roger L [0000-0001-5764-7268], Moreno, Victor [0000-0002-2818-5487], Muir, Kenneth [0000-0001-6429-988X], Nathanson, Katherine L [0000-0002-6740-0901], Nevanlinna, Heli [0000-0002-0916-2976], Newcomb, Polly A [0000-0001-8786-0043], Nikitina-Zake, Liene [0000-0003-2491-5187], Nordestgaard, Børge G [0000-0002-1954-7220], Olama, Ali Amin Al [0000-0002-7178-3431], Olopade, Olufunmilayo I [0000-0002-9936-1599], Pashayan, Nora [0000-0003-0843-2468], Parsons, Michael T [0000-0003-3242-8477], Plaseska-Karanfilska, Dijana [0000-0001-8877-2416], Raskin, Leon [0000-0003-1195-7214], Rennert, Gad [0000-0002-8512-068X], Risch, Angela [0000-0002-8026-5505], Roobol, Monique J [0000-0001-6967-1708], Saloustros, Emmanouil [0000-0002-0485-0120], Schabath, Matthew B [0000-0003-3241-3216], Schleutker, Johanna [0000-0002-1863-0305], Schmidt, Marjanka K [0000-0002-2228-429X], Sorensen, Karina Dalsgaard [0000-0002-4902-5490], Stintzing, Sebastian [0000-0002-3297-5801], Stone, Jennifer [0000-0001-5077-0124], Tardon, Adonina [0000-0001-5150-1209], Teixeira, Manuel R [0000-0002-4896-5982], Toland, Amanda E [0000-0002-0271-1792], Aguado-Barrera, Miguel Elías [0000-0002-7822-6726], Webb, Penelope M [0000-0003-0733-5930], Wolk, Alicja [0000-0001-7387-6845], Yannoukakos, Drakoulis [0000-0001-7509-3510], Zheng, Wei [0000-0003-1226-070X], Ziogas, Argyrios [0000-0003-4529-3727], Peters, Ulrike [0000-0001-5666-9318], Eeles, Rosalind A [0000-0002-3698-6241], Brennan, Paul J [0000-0002-0518-8714], Easton, Douglas F [0000-0003-2444-3247], Pharoah, Paul DP [0000-0001-8494-732X], Price, Alkes L [0000-0002-2971-7975], Apollo - University of Cambridge Repository, Institut Català de la Salut, [Jiang X] Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. [Finucane HK] Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [Schumacher FR] Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA. Seidman Cancer Center, University Hospitals, Cleveland, OH, USA. [Schmit SL] Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. [Tyrer JP] Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK. [Han Y] Department of Biomedical Data Science, The Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. [Diez O] Grup d'Oncogenètica, Vall d'Hebron Institut d'Oncologia, Barcelona, Spain. Hospital Universitari Vall d'Hebron, Barcelona, Spain, Hospital Universitari Vall d'Hebron, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, Tampere University, Cancer Research UK (Reino Unido), NIHR - Comprehensive Biomedical Research Centre, Guy ’ s & St. Thomas ’ NHS Foundation Trust, NIHR - Oxford Biomedical Research Centre (Reino Unido), German Cancer Research Center, Consejo Nacional de Ciencia y Tecnología (CONACyT), King College London, National Health and Medical Research Council (Australia), Canadian Institutes of Health Research, The BREast Oncology GAlician Network (BREOGAN, Dietmar-Hopp Foundation, Helmholtz Society and the German Cancer Research Center (DKFZ), Asociación Española Contra el Cáncer, Vall d'Hebron Barcelona Hospital Campus, Clinicum, Department of Oncology, University of Helsinki, Department of Pathology, Medicum, Department of Obstetrics and Gynecology, and HUS Comprehensive Cancer Center
Subjects: Oncology, Male, Lung Neoplasms, Colorectal cancer, Epidemiology, Inheritance Patterns, Genome-wide association study, 02 engineering and technology, Colorectal Neoplasms/diagnosis, Càncer - Aspectes genètics, 0302 clinical medicine, Neoplasm Proteins/genetics, Brjóstakrabbamein, PARTITIONING HERITABILITY, lcsh:Science, Càncer, Cancer genetics, Cancer, Càncer - Estudi de casos, Ovarian Neoplasms, Prostatic Neoplasms/diagnosis, 0303 health sciences, Otros calificadores::Otros calificadores::/genética [Otros calificadores], 1184 Genetics, developmental biology, physiology, Genomics, Publisher Correction, ddc, 3. Good health, Neoplasm Proteins, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Etiologia, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Neoplasias [ENFERMEDADES], ICEP, Erfðarannsóknir, 0210 nano-technology, Genetic Phenomena::Inheritance Patterns [PHENOMENA AND PROCESSES], medicine.medical_specialty, Biolääketieteet - Biomedicine, Science, Lung Neoplasms/diagnosis, European Continental Ancestry Group, Genetic correlation, Article, General Biochemistry, Genetics and Molecular Biology, White People, GENETIC ARCHITECTURE, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Syöpätaudit - Cancers, BREAST-CANCER, Humans, Otros calificadores::Otros calificadores::Otros calificadores::/etnología [Otros calificadores], Polymorphism, GENOME-WIDE ASSOCIATION, solid cancers, heritability, enrichment, Settore MED/42 - IGIENE GENERALE E APPLICATA, ResearchInstitutes_Networks_Beacons/mcrc, Fenómenos Genéticos::Patrón de Herencia [FENÓMENOS Y PROCESOS], ANALYSES IDENTIFY, Biology and Life Sciences, fenómenos genéticos::patrones de herencia [FENÓMENOS Y PROCESOS], medicine.disease, Càncer -- Etiologia, 030104 developmental biology, Case-Control Studies, RISK-FACTORS, lcsh:Q, 0301 basic medicine, Etiology, Medizin, General Physics and Astronomy, técnicas de investigación::métodos epidemiológicos::características de los estudios epidemiológicos::estudios epidemiológicos::estudios de casos y controles [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], head and neck, Prostate cancer, Medicine and Health Sciences, Càncer -- Aspectes genètics, Multidisciplinary, Manchester Cancer Research Centre, Mental Disorders, Codi genètic, Smoking, Single Nucleotide, 021001 nanoscience & nanotechnology, Phenotype, Centre for Surgical Research, Cancer -- Etiology, MENDELIAN RANDOMIZATION, Female, Smoking/ethnology, Colorectal Neoplasms, Mental Disorders/ethnology, Medical Genetics, Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics::Epidemiologic Studies::Case-Control Studies [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES AND EQUIPMENT], Cancer Etiology, Técnicas de Investigación::Métodos Epidemiológicos::Características de Estudios Epidemiológicos::Estudios Epidemiológicos::Estudios de Casos y Controles [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], SUSCEPTIBILITY LOCI, 3122 Cancers, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, LUNG-CANCER, All institutes and research themes of the Radboud University Medical Center, Internal medicine, MD Multidisciplinary, Other subheadings::Other subheadings::/genetics [Other subheadings], medicine, Erfðafræði, Genetic Predisposition to Disease, CELL-TYPES, Lung cancer, Krabbamein, Medicinsk genetik, 030304 developmental biology, Ovarian Neoplasms/diagnosis, Faraldsfræði, Prostatic Neoplasms, Breast Neoplasms/diagnosis, General Chemistry, Heritability, Head and Neck Neoplasms/diagnosis, Neoplasms [DISEASES], Genome-Wide Association Study, 3111 Biomedicine, Ovarian cancer, Other subheadings::Other subheadings::Other subheadings::/ethnology [Other subheadings]
Abstract: Publisher's version (útgefin grein)., Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10−8), breast and ovarian cancer (rg = 0.24, p = 7 × 10−5), breast and lung cancer (rg = 0.18, p =1.5 × 10−6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10−4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis., The authors in this manuscript were working on behalf of BCAC, CCFR, CIMBA, CORECT, GECCO, OCAC, PRACTICAL, CRUK, BPC3, CAPS, PEGASUS, TRICL-ILCCO, ABCTB, APCB, BCFR, CONSIT TEAM, EMBRACE, GC-HBOC, GEMO, HEBON, kConFab/AOCS Mod SQuaD, and SWE-BRCA. The breast cancer genome-wide association analyses: BCAC is funded by Cancer Research UK [C1287/A16563, C1287/A10118], the European Union’s Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633784 for BRIDGES and B-CAST, respectively), and by the European Community’s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). The EU Horizon 2020 Research and Innovation Programme funding source had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Genotyping of the OncoArray was funded by the NIH Grant U19 CA148065, and Cancer UK Grant C1287/A16563 and the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344) and, the Ministère de l’Économie, Science et Innovation du Québec through Genome Québec and the PSR-SIIRI-701 grant, and the Quebec Breast Cancer Foundation. Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112—the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, and Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The DRIVE Consortium was funded by U19 CA148065. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. M.C.S. is a NHMRC Senior Research Fellow. The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]. The Australian Breast Cancer Tissue Bank (ABCTB) is generously supported by the National Health and Medical Research Council of Australia, The Cancer Institute NSW and the National Breast Cancer Foundation. The ACP study is funded by the Breast Cancer Research Trust, UK. The AHS study is supported by the intramural research program of the National Institutes of Health, the National Cancer Institute (grant number Z01-CP010119), and the National Institute of Environmental Health Sciences (grant number Z01-ES049030). The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breast Cancer Now and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The BCEES was funded by the National Health and Medical Research Council, Australia and the Cancer Council Western Australia and acknowledges funding from the National Breast Cancer Foundation (JS). For the BCFR-NY, BCFR-PA, and BCFR-UT this work was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. For BIGGS, ES is supported by NIHR Comprehensive Biomedical Research Centre, Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London, United Kingdom. IT is supported by the Oxford Biomedical Research Centre. BOCS is supported by funds from Cancer Research UK (C8620/A8372/A15106) and the Institute of Cancer Research (UK). BOCS acknowledges NHS funding to the Royal Marsden/Institute of Cancer Research NIHR Specialist Cancer Biomedical Research Centre. The BREast Oncology GAlician Network (BREOGAN) is funded by Acción Estratégica de Salud del Instituto de Salud Carlos III FIS PI12/02125/Cofinanciado FEDER; Acción Estratégica de Salud del Instituto de Salud Carlos III FIS Intrasalud (PI13/01136); Programa Grupos Emergentes, Cancer Genetics Unit, Instituto de Investigacion Biomedica Galicia Sur. Xerencia de Xestion Integrada de Vigo-SERGAS, Instituto de Salud Carlos III, Spain; Grant 10CSA012E, Consellería de Industria Programa Sectorial de Investigación Aplicada, PEME I + D e I + D Suma del Plan Gallego de Investigación, Desarrollo e Innovación Tecnológica de la Consellería de Industria de la Xunta de Galicia, Spain; Grant EC11-192. Fomento de la Investigación Clínica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain; and Grant FEDER-Innterconecta. Ministerio de Economia y Competitividad, Xunta de Galicia, Spain. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CAMA study was funded by Consejo Nacional de Ciencia y Tecnología (CONACyT) (SALUD-2002-C01-7462). Sample collection and processing was funded in part by grants from the National Cancer Institute (NCI R01CA120120 and K24CA169004). CBCS is funded by the Canadian Cancer Society (grant # 313404) and the Canadian Institutes of Health Research. CCGP is supported by funding from the University of Crete. The CECILE study was supported by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Agence Nationale de Sécurité Sanitaire, de l’Alimentation, de l’Environnement et du Travail (ANSES), Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev and Gentofte Hospital. The CNIO-BCS was supported by the Instituto de Salud Carlos III, the Red Temática de Investigación Cooperativa en Cáncer and grants from the Asociación Española Contra el Cáncer and the Fondo de Investigación Sanitario (PI11/00923 and PI12/00070). COLBCCC is supported by the German Cancer Research Center (DKFZ), Heidelberg, Germany. D.T. was in part supported by a postdoctoral fellowship from the Alexander von Humboldt Foundation. The American Cancer Society funds the creation, maintenance, and updating of the CPS-II cohort. The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398, UM1 CA164917, and U01 CA199277). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. H.A.C eceives support from the Lon V Smith Foundation (LVS39420). The University of Westminster curates the DietCompLyf database funded by Against Breast Cancer Registered Charity No. 1121258 and the NCRN. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by: Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation, the Stavros Niarchos Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). FHRISK is funded from NIHR grant PGfAR 0707-10031. The GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer) is supported by the German Cancer Aid (grant no 110837, coordinator: Rita K. Schmutzler, Cologne). This work was also funded by the European Regional Development Fund and Free State of Saxony, Germany (LIFE - Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/2470, and 14575/2470). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0, and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The GEPARSIXTO study was conducted by the German Breast Group GmbH. The GESBC was supported by the Deutsche Krebshilfe e. V. [70492] and the German Cancer Research Center (DKFZ). GLACIER was supported by Breast Cancer Now, CRUK and Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The HABCS study was supported by the Claudia von Schilling Foundation for Breast Cancer Research, by the Lower Saxonian Cancer Society, and by the Rudolf-Bartling Foundation. The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, and the Sigrid Juselius Foundation. The HERPACC was supported by MEXT Kakenhi (No. 170150181 and 26253041) from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from Ministry Health, Labour and Welfare of Japan, by Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan, by National Cancer Center Research and Development Fund, and “Practical Research for Innovative Cancer Control (15ck0106177h0001)” from Japan Agency for Medical Research and development, AMED, and Cancer Bio Bank Aichi. The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. The HUBCS was supported by a grant from the German Federal Ministry of Research and Education (RUS08/017), and by the Russian Foundation for Basic Research and the Federal Agency for Scientific Organizations for support the Bioresource collections and RFBR grants 14-04-97088, 17-29-06014, and 17-44-020498. ICICLE was supported by Breast Cancer Now, CRUK, and Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (A.L.F.) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and Bert von Kantzows foundation. The KARMA study was supported by Märit and Hans Rausings Initiative Against Breast Cancer. The KBCP was financially supported by the special Government Funding (E.V.O.) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). G.C.-T. and P.W. are supported by the NHMRC. RB was a Cancer Institute NSW Clinical Research Fellow. The KOHBRA study was partially supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 1020350; 1420190). LAABC is supported by grants (1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP) which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute’s Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403. L.M.B.C. is supported by the ‘Stichting tegen Kanker’. D.L. is supported by the FWO. The MABCS study is funded by the Research Centre for Genetic Engineering and Biotechnology “Georgi D. Efremov” and supported by the German Academic Exchange Program, DAAD. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419, 110826, 110828], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects “5 × 1000”). The MCBCS was supported by the NIH grants CA192393, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057 and 396414, and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. The MEC was support by NIH grants CA63464, CA54281, CA098758, CA132839, and CA164973. The MISS study is supported by funding from ERC-2011-294576 Advanced grant, Swedish Cancer Society, Swedish Research Council, Local hospital funds, Berta Kamprad Foundation, Gunnar Nilsson. The MMHS study was supported by NIH grants CA97396, CA128931, CA116201, CA140286, and CA177150. MSKCC is supported by grants from the Breast Cancer Research Foundation and Robert and Kate Niehaus Clinical Cancer Genetics Initiative. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program – grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. MYBRCA is funded by research grants from the Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Malaysia. MYMAMMO is supported by research grants from Yayasan Sime Darby LPGA Tournament and Malaysian Ministry of Higher Education (RP046B-15HTM). The NBCS has been supported by the Research Council of Norway grant 193387/V50 (to A.-L. Børresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A.-L. Børresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (grant 39346 to A.-L. Børresen-Dale and 27208 to V.N. Kristensen) and the Norwegian Cancer Society (to A.-L. Børresen-Dale and 419616 - 71248 - PR-2006-0282 to V.N. Kristensen). It has received funding from the K.G. Jebsen Centre for Breast Cancer Research (2012-2015). The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The Northern California Breast Cancer Family Registry (NC-BCFR) and Ontario Familial Breast Cancer Registry (OFBCR) were supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The Carolina Breast Cancer Study was funded by Komen Foundation, the National Cancer Institute (P50 CA058223, U54 CA156733, and U01 CA179715), and the North Carolina University Cancer Research Fund. The NGOBCS was supported by Grants-in-Aid for the Third Term Comprehensive Ten-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan, and for Scientific Research on Priority Areas, 17015049 and for Scientific Research on Innovative Areas, 221S0001, from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The NHS was supported by NIH grants P01 CA87969, UM1 CA186107, and U19 CA148065. The NHS2 was supported by NIH grants UM1 CA176726 and U19 CA148065. The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation, and the special Governmental EVO funds for Oulu University Hospital-based research activities. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. Genotyping for PLCO was supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. The POSH study is funded by Cancer Research UK (grants C1275/A11699, C1275/C22524, C1275/A19187, C1275/A15956, and Breast Cancer Campaign 2010PR62, 2013PR044. PROCAS is funded from NIHR grant PGfAR 0707-10031. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The SBCGS was supported primarily by NIH grants R01CA64277, R01CA148667, UMCA182910, and R37CA70867. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The scientific development and funding of this project were, in part, supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network U19 CA148065. The SBCS was supported by Sheffield Experimental Cancer Medicine Centre and Breast Cancer Now Tissue Bank. The SCCS is supported by a grant from the National Institutes of Health (R01 CA092447). Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, KY; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry, 4815 W. Markham, Little Rock, AR 72205. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. SEARCH is funded by Cancer Research UK [C490/A10124, C490/A16561] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve. SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). SGBCC is funded by the NUS start-up Grant, National University Cancer Institute Singapore (NCIS) Centre Grant and the NMRC Clinician Scientist Award. Additional controls were recruited by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC), which was funded by the Biomedical Research Council, grant number: 05/1/21/19/425. The Sister Study (SISTER) is supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES049033). The Two Sister Study (2SISTER) was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES102245), and, also by a grant from Susan G. Komen for the Cure, grant FAS0703856. SKKDKFZS is supported by the DKFZ. The SMC is funded by the Swedish Cancer Foundation. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. The TBCS was funded by The National Cancer Institute, Thailand. The TNBCC was supported by a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation. The TWBCS is supported by the Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan. The UCIBCS component of this research was supported by the NIH [CA58860, CA92044] and the Lon V Smith Foundation [LVS39420]. The UKBGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The US3SS study was supported by Massachusetts (K.M.E., R01CA47305), Wisconsin (P.A.N., R01 CA47147) and New Hampshire (L.T.-E., R01CA69664) centers, and Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The USRT Study was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The WAABCS study was supported by grants from the National Cancer Institute of the National Institutes of Health (R01 CA89085 and P50 CA125183 and the D43 TW009112 grant), Susan G. Komen (SAC110026), the Dr. Ralph and Marian Falk Medical Research Trust, and the Avon Foundation for Women. The WHI program is funded by the National Heart, Lung, and Blood Institute, the US National Institutes of Health and the US Department of Health and Human Services (HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C). This work was also funded by NCI U19 CA148065-01. D.G.E. is supported by the all Manchester NIHR Biomedical research center Manchester (IS-BRC-1215-20007). HUNBOCS, Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grant KTIA-OTKA CK-80745, NKFI_OTKA K-112228. C.I. received support from the Nontherapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI P30-CA-51008) and the Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research. K.M. is supported by CRUK C18281/A19169. City of Hope Clinical Cancer Community Research Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J Weitzel) from the National Cancer Institute and the office of the Directory, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The colorectal cancer genome-wide association analyses: Colorectal Transdisciplinary Study (CORECT): The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CORECT Consortium, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the CORECT Consortium. We are incredibly grateful for the contributions of Dr. Brian Henderson and Dr. Roger Green over the course of this study and acknowledge them in memoriam. We are also grateful for support from Daniel and Maryann Fong. ColoCare: we thank the many investigators and staff who made this research possible in ColoCare Seattle and ColoCare Heidelberg. ColoCare was initiated and developed at the Fred Hutchinson Cancer Research Center by Drs. Ulrich and Grady. CCFR: the Colon CFR graciously thanks the generous contributions of their study participants, dedication of study staff, and financial support from the U.S. National Cancer Institute, without which this important registry would not exist. Galeon: GALEON wishes to thank the Department of Surgery of University Hospital of Santiago (CHUS), Sara Miranda Ponte, Carmen M Redondo, and the staff of the Department of Pathology and Biobank of CHUS, Instituto de Investigación Sanitaria de Santiago (IDIS), Instituto de Investigación Sanitaria Galicia Sur (IISGS), SERGAS, Vigo, Spain, and Programa Grupos Emergentes, Cancer Genetics Unit, CHUVI Vigo Hospital, Instituto de Salud Carlos III, Spain. MCCS: this study was made possible by the contribution of many people, including the original investigators and the diligent team who recruited participants and continue to work on follow-up. We would also like to express our gratitude to the many thousands of Melbourne residents who took part in the study and provided blood samples. SEARCH: We acknowledge the contributions of Mitul Shah, Val Rhenius, Sue Irvine, Craig Luccarini, Patricia Harrington, Don Conroy, Rebecca Mayes, and Caroline Baynes. The Swedish low-risk colorectal cancer study: we thank Berith Wejderot and the Swedish low-risk colorectal cancer study group. Genetics & Epidemiology of Colorectal Cancer Consortium (GECCO): we thank all those at the GECCO Coordinating Center for helping bring together the data and people that made this project possible. ASTERISK: we are very grateful to Dr. Bruno Buecher without whom this project would not have existed. We also thank all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians and students. DACHS: we thank all participants and cooperating clinicians, and Ute Handte-Daub, Renate Hettler-Jensen, Utz Benscheid, Muhabbet Celik, and Ursula Eilber for excellent technical assistance. HPFS, NHS and PHS: we acknowledge Patrice Soule and Hardeep Ranu of the Dana-Farber Harvard Cancer Center High-Throughput Polymorphism Core who assisted in the genotyping for NHS, HPFS, and PHS under the supervision of Dr. Immaculata Devivo and Dr. David Hunter, Qin (Carolyn) Guo, and Lixue Zhu who assisted in programming for NHS and HPFS and Haiyan Zhang who assisted in programming for the PHS. We thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-Up Study, for their valuable contributions as well as the following state cancer registries for their help: A.L., A.Z., A.R., C.A., C.O., C.T., D.E., F.L., G.A., I.D., I.L., I.N., I.A., K.Y., L.A., M.E., M.D., M.A., M.I., N.E., N.H., N.J., N.Y., N.C., N.D., O.H., O.K., O.R., P.A., R.I., S.C., T.N., T.X., V.A., W.A., W.Y. In addition, this study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Certain data used in this publication were obtained from the DPH. We assume full responsibility for analyses and interpretation of these data. PLCO: we thank Drs. Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Center investigators and staff or the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, Mr. Tom Riley and staff, Information Management Services Inc., Ms. Barbara O’Brien and staff, Westat Inc. and Drs. Bill Kopp, Wen Shao and staff, SAIC-Frederick. Most importantly, we acknowledge the study participants for their contributions for making this study possible. The statements contained herein are solely those of the authors and do not represent or imply concurrence or endorsement by NCI. PMH: we thank the study participants and staff of the Hormones and Colon Cancer study. WHI: we thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short20List.pdf. CORECT: The CORECT Study was supported by the National Cancer Institute, National Institutes of Health (NCI/NIH), U.S. Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350; P01 CA196569; and R01 CA201407) and National Institutes of Environmental Health Sciences, National Institutes of Health (grant number T32 ES013678). The ATBC Study was supported by the US Public Health Service contracts (N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C) from the National Cancer Institute. The Cancer Prevention Study-II Nutrition Cohort is funded by the American Cancer Society. ColoCare: This work was supported by the National Institutes of Health (grant numbers R01 CA189184, U01 CA206110, 2P30CA015704-40 (Gilliland)), the Matthias Lackas-Foundation, the German Consortium for Translational Cancer Research, and the EU TRANSCAN initiative. Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): funding for GECCO was provided by the National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (grant numbers U01 CA137088, R01 CA059045, and U01 CA164930). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. The Colon Cancer Family Registry (CFR) Illumina GWAS was supported by funding from the National Cancer Institute, National Institutes of Health (grant numbers U01 CA122839, R01 CA143247). The Colon CFR/CORECT Affymetrix Axiom GWAS and OncoArray GWAS were supported by funding from National Cancer Institute, National Institutes of Health (grant number U19 CA148107 to S.G.). The Colon CFR participant recruitment and collection of data and biospecimens used in this study were supported by the National Cancer Institute, National Institutes of Health (grant number UM1 CA167551) and through cooperative agreements with the following Colon CFR centers: Australasian Colorectal Cancer Family Registry (NCI/NIH grant numbers U01 CA074778 and U01/U24 CA097735), USC Consortium Colorectal Cancer Family Registry (NCI/NIH grant numbers U01/U24 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (NCI/NIH grant number U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (NCI/NIH grant number U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074794), and University of Hawaii Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074806), Additional support for case ascertainment was provided from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute to Fred Hutchinson Cancer Research Center (Control Nos. N01-CN-67009 and N01-PC-35142, and Contract No. HHSN2612013000121), the Hawai’i Department of Health (Control Nos. N01-PC-67001 and N01-PC-35137, and Contract No. HHSN26120100037C, and the California Department of Public Health (contracts HHSN261201000035C awarded to the University of Southern California, and the following state cancer registries: A.Z., C.O., M.N., N.C., N.H., and by the Victoria Cancer Registry and Ontario Cancer Registry. ESTHER/VERDI was supported by grants from the Baden–Württemberg Ministry of Science, Research and Arts and the German Cancer Aid. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. GALEON: FIS Intrasalud (PI13/01136). The MCCS was further supported by Australian NHMRC grants 509348, 209057, 251553, and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. MSKCC: the work at Sloan Kettering in New York was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. Moffitt: This work was supported by funding from the National Institutes of Health (grant numbers R01 CA189184, P30 CA076292), Florida Department of Health Bankhead-Coley Grant 09BN-13, and the University of South Florida Oehler Foundation. Moffitt contributions were supported in part by the Total Cancer Care Initiative, Collaborative Data Services Core, and Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, a National Cancer Institute-designated Comprehensive Cancer Center (grant number P30 CA076292). SEARCH: Cancer Research UK (C490/A16561). The Spanish study was supported by Instituto de Salud Carlos III, co-funded by FEDER funds –a way to build Europe– (grants PI14-613 and PI09-1286), Catalan Government DURSI (grant 2014SGR647), and Junta de Castilla y León (grant LE22A10-2). The Swedish Low-risk Colorectal Cancer Study: the study was supported by grants from the Swedish research council; K2015-55 × -22674-01-4, K2008-55 × -20157-03-3, K2006-72 × -20157-01-2 and the Stockholm County Council (ALF project). CIDR genotyping for the Oncoarray was conducted under contract 268201200008I (to K.D.), through grant 101HG007491-01 (to C.I.A.). The Norris Cotton Cancer Center - P30CA023108, The Quantitative Biology Research Institute - P20GM103534, and the Coordinating Center for Screen Detected Lesions - U01CA196386 also supported efforts of C.I.A. This work was also supported by the National Cancer Institute (grant numbers U01 CA1817700, R01 CA144040). ASTERISK: a Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). COLO2&3: National Institutes of Health (grant number R01 CA060987). DACHS: This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1, and BR 1704/17-1), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A, and 01ER1505B). DALS: National Institutes of Health (grant number R01 CA048998 to M.L.S). HPFS is supported by National Institutes of Health (grant numbers P01 CA055075, UM1 CA167552, R01 137178, and P50 CA127003), NHS by the National Institutes of Health (grant numbers UM1 CA186107, R01 CA137178, P01 CA087969, and P50 CA127003), NHSII by the National Institutes of Health (grant numbers R01 050385CA and UM1 CA176726), and PHS by the National Institutes of Health (grant number R01 CA042182). MEC: National Institutes of Health (grant numbers R37 CA054281, P01 CA033619, and R01 CA063464). OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (grant number U01 CA074783); see Colon CFR section above. As subset of ARCTIC, OFCCR is supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. T.J.H. and B.W.Z. are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Additionally, a subset of control samples was genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS, Colon CGEMS pancreatic cancer scan (PanScan), and the Lung Cancer and Smoking study. The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093.v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, 23 and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. PMH: National Institutes of Health (grant number R01 CA076366). VITAL: National Institutes of Health (grant number K05-CA154337). WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. The head and neck cancer genome-wide association analyses: The study was supported by NIH/NCI: P50 CA097190, and P30 CA047904, Canadian Cancer Society Research Institute (no. 020214) and Cancer Care Ontario Research Chair to R.H. The Princess Margaret Hospital Head and Neck Cancer Translational Research Program is funded by the Wharton family, Joe’s Team, Gordon Tozer, Bruce Galloway and the Elia family. Geoffrey Liu was supported by the Posluns Family Fund and the Lusi Wong Family Fund at the Princess Margaret Foundation, and the Alan B. Brown Chair in Molecular Genomics. This publication presents data from Head and Neck 5000 (H&N5000). H&N5000 was a component of independent research funded by the UK National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Human papillomavirus (HPV) in H&N5000 serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). National Cancer Institute (R01-CA90731); National Institute of Environmental Health Sciences (P30ES10126). The authors thank all the members of the GENCAPO team/The Head and Neck Genome Project (GENCAPO) was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (Grant numbers 04/12054-9 and 10/51168-0). CPS-II recruitment and maintenance is supported with intramural research funding from the American Cancer Society. Genotyping performed at the Center for Inherited Disease Research (CIDR) was funded through the U.S. National Institute of Dental and Craniofacial Research (NIDCR) grant 1 × 01HG007780-0. The University of Pittsburgh head and neck cancer case-control study is supported by National Institutes of Health grants P50 CA097190 and P30 CA047904. The Carolina Head and Neck Cancer Study (CHANCE) was supported by the National Cancer Institute (R01-CA90731). The Head and Neck Genome Project (GENCAPO) was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (Grant numbers 04/12054-9 and 10/51168-0). The authors thank all the members of the GENCAPO team. The HN5000 study was funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10034), the views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The Toronto study was funded by the Canadian Cancer Society Research Institute (020214) and the National Cancer Institute (U19-CA148127) and the Cancer Care Ontario Research Chair. The alcohol-related cancers and genetic susceptibility study in Europe (ARCAGE) was funded by the European Commission’s 5th Framework Program (QLK1-2001-00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte, and Padova University (CPDA057222). The Rome Study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) IG 2011 10491 and IG2013 14220 to S.B., and Fondazione Veronesi to S.B. The IARC Latin American study was funded by the European Commission INCO-DC programme (IC18-CT97-0222), with additional funding from Fondo para la Investigacion Cientifica y Tecnologica (Argentina) and the Fundação de Amparo à Pesquisa do Estado de São Paulo (01/01768-2). We thank Leticia Fernandez, Instituto Nacional de Oncologia y Radiobiologia, La Habana, Cuba and Sergio and Rosalina Koifman, for their efforts with the IARC Latin America study São Paulo center. The IARC Central Europe study was supported by European Commission’s INCO-COPERNICUS Program (IC15- CT98-0332), NIH/National Cancer Institute grant CA92039, and the World Cancer Research Foundation grant WCRF 99A28. The IARC Oral Cancer Multicenter study was funded by grant S06 96 202489 05F02 from Europe against Cancer; grants FIS 97/0024, FIS 97/0662, and BAE 01/5013 from Fondo de Investigaciones Sanitarias, Spain; the UICC Yamagiwa-Yoshida Memorial International Cancer Study; the National Cancer Institute of Canada; Associazione Italiana per la Ricerca sul Cancro; and the Pan-American Health Organization. Coordination of the EPIC study is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The lung cancer genome-wide association analyses: Transdisciplinary Research for Cancer in Lung (TRICL) of the International Lung Cancer Consortium (ILCCO) was supported by (U19-CA148127, CA148127S1, U19CA203654, and Cancer Prevention Research Institute of Texas RR170048). The ILCCO data harmonization is supported by Cancer Care Ontario Research Chair of Population Studies to R. H. and Lunenfeld-Tanenbaum Research Institute, Sinai Health System. The TRICL-ILCCO OncoArray was supported by in-kind genotyping by the Centre for Inherited Disease Research (26820120008i-0-26800068-1). The CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02-67 and FICYT IB09-133, and the University Institute of Oncology (IUOPA), of the University of Oviedo and the Ciber de Epidemiologia y Salud Pública. CIBERESP, SPAIN. The work performed in the CARET study was supported by the National Institute of Health/National Cancer Institute: UM1 CA167462 (PI: Goodman), National Institute of Health UO1-CA6367307 (PIs Omen, Goodman); National Institute of Health R01 CA111703 (PI Chen), National Institute of Health 5R01 CA151989-01A1(PI Doherty). The Liverpool Lung project is supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by the NIH (National Cancer Institute) grants CA092824, CA090578, CA074386. The Multi-ethnic Cohort Study was partially supported by NIH Grants CA164973, CA033619, CA63464, and CA148127. The work performed in MSH-PMH study was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. NJLCS was funded by the State Key Program of National Natural Science of China (81230067), the National Key Basic Research Program Grant (2011CB503805), the Major Program of the National Natural Science Foundation of China (81390543). The Norway study was supported by Norwegian Cancer Society, Norwegian Research Council. The Shanghai Cohort Study (SCS) was supported by National Institutes of Health R01 CA144034 (PI: Yuan) and UM1 CA182876 (PI: Yuan). The Singapore Chinese Health Study (SCHS) was supported by National Institutes of Health R01 CA144034 (PI: Yuan) and UM1 CA182876 (PI: Yuan). The work in TLC study has been supported in part the James & Esther King Biomedical Research Program (09KN-15), National Institutes of Health Specialized Programs of Research Excellence (SPORE) Grant (P50 CA119997), and by a Cancer Center Support Grant (CCSG) at the H. Lee Moffitt Cancer Center and Research Institute, an NCI designated Comprehensive Cancer Center (grant number P30-CA76292). The Vanderbilt Lung Cancer Study—BioVU dataset used for the analyses described was obtained from Vanderbilt University Medical Center’s BioVU, which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the Vanderbilt CTSA grant UL1TR000445 from NCATS/NIH. Dr. Aldrich was supported by NIH/National Cancer Institute K07CA172294 (PI: Aldrich) and Dr. Bush was supported by NHGRI/NIH U01HG004798 (PI: Crawford). The Copenhagen General Population Study (CGPS) was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The NELCS study: Grant Number P20RR018787 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). The Kentucky Lung Cancer Research Initiative was supported by the Department of Defense [Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program] under award number: 10153006 (W81XWH-11-1-0781). Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. This research was also supported by unrestricted infrastructure funds from the UK Center for Clinical and Translational Science, NIH grant UL1TR000117 and Markey Cancer Center NCI Cancer Center Support Grant (P30 CA177558) Shared Resource Facilities: Cancer Research Informatics, Biospecimen and Tissue Procurement, and Biostatistics and Bioinformatics. The M.D. Anderson Cancer Center study was supported in part by grants from the NIH (P50 CA070907, R01 CA176568) (to X.W.), Cancer Prevention & Research Institute of Texas (RP130502) (to X.W.), and The University of Texas MD Anderson Cancer Center institutional support for the Center for Translational and Public Health Genomics. The deCODE study of smoking and nicotine dependence was funded in part by a grant from NIDA (R01- DA017932). The study in Lodz center was partially funded by Nofer Institute of Occupational Medicine, under task NIOM 10.13: Predictors of mortality from non-small cell lung cancer—field study. Genetic sharing analysis was funded by NIH grant CA194393. The research undertaken by M.D.T., L.V.W., and M.S.A. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. M.D.T. holds a Medical Research Council Senior Clinical Fellowship (G0902313). The work to assemble the FTND GWAS meta-analysis was supported by the National Institutes of Health (NIH), National Institute on Drug Abuse (NIDA) grant number R01 DA035825 (Principal Investigator [PI]: DBH). The study populations included COGEND (dbGaP phs000092.v1.p1 and phs000404.v1.p1), COPDGene (dbGaP phs000179.v3.p2), deCODE Genetics, EAGLE (dbGaP phs000093.vs.p2), and SAGE. dbGaP phs000092.v1.p1). See Hancock et al. Transl Psychiatry 2015 (PMCID: PMC4930126) for the full listing of funding sources and other acknowledgments. The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT)study was funded by the Sheffield Hospitals Charity, Sheffield Experimental Cancer Medicine Centre and Weston Park Hospital Cancer Charity. The ovarian cancer genome-wide association analysis: The Ovarian Cancer Association Consortium (OCAC) is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium that was funded by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7). The OCAC OncoArray genotyping project was funded through grants from the U.S. National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.), and R01-CA058598 (M.T.G.); Canadian Institutes of Health Research (MOP-86727 (L.E.K.) and the Ovarian Cancer Research Fund (A.B.). The COGS project was funded through a European Commission’s Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175) and through a grant from the U.S. National Institutes of Health (R01-CA122443 (E.L.G)). Funding for individual studies: AAS: National Institutes of Health (RO1-CA142081); AOV: The Canadian Institutes for Health Research (MOP-86727); AUS: The Australian Ovarian Cancer Study Group was supported by the U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), National Health & Medical Research Council of Australia (199600, 400413 and 400281), Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania and Cancer Foundation of Western Australia (Multi-State Applications 191, 211, and 182). The Australian Ovarian Cancer Study gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation; BAV: ELAN Funds of the University of Erlangen-Nuremberg; BEL: National Kankerplan; BGS: Breast Cancer Now, Institute of Cancer Research; BVU: Vanderbilt CTSA grant from the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) (ULTR000445); CAM: National Institutes of Health Research Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Cancer Centre; CHA: Innovative Research Team in University (PCSIRT) in China (IRT1076); CNI: Instituto de Salud Carlos III (PI12/01319); Ministerio de Economía y Competitividad (SAF2012); COE: Department of Defense (W81XWH-11-2-0131); CON: National Institutes of Health (R01-CA063678, R01-CA074850; and R01-CA080742); DKE: Ovarian Cancer Research Fund; DOV: National Institutes of Health R01-CA112523 and R01-CA87538; EMC: Dutch Cancer Society (EMC 2014-6699); EPC: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom); GER: German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research (01 GB 9401) and the German Cancer Research Center (DKFZ); GRC: This research has been co-financed by the European Union (European Social Fund—ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF)—Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund; GRR: Roswell Park Cancer Institute Alliance Foundation, P30 CA016056; HAW: U.S. National Institutes of Health (R01-CA58598, N01-CN-55424, and N01-PC-67001); HJO: Intramural funding; Rudolf-Bartling Foundation; HMO: Intramural funding; Rudolf-Bartling Foundation; HOC: Helsinki University Research Fund; HOP: Department of Defense (DAMD17-02-1-0669) and NCI (K07-CA080668, R01-CA95023, P50-CA159981 MO1-RR000056 R01-CA126841); HUO: Intramural funding; Rudolf-Bartling Foundation; JGO: JSPS KAKENHI grant; JPN: Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare; KRA: This study (Ko-EVE) was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 0920010); LAX: American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124; LUN: ERC-2011-AdG 294576-risk factors cancer, Swedish Cancer Society, Swedish Research Council, Beta Kamprad Foundation; MAC: National Institutes of Health (R01-CA122443, P30-CA15083, P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; Fraternal Order of Eagles; MAL: Funding for this study was provided by research grant R01- CA61107 from the National Cancer Institute, Bethesda, MD, research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark; and the Mermaid I project; MAS: Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; MAY: National Institutes of Health (R01-CA122443, P30-CA15083, and P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; MCC: Cancer Council Victoria, National Health and Medical Research Council of Australia (NHMRC) grants number 209057, 251533, 396414, and 504715; MDA: DOD Ovarian Cancer Research Program (W81XWH-07-0449); MEC: NIH (CA54281, CA164973, CA63464); MOF: Moffitt Cancer Center, Merck Pharmaceuticals, the state of Florida, Hillsborough County, and the city of Tampa; NCO: National Institutes of Health (R01-CA76016) and the Department of Defense (DAMD17-02-1-0666); NEC: National Institutes of Health R01-CA54419 and P50-CA105009 and Department of Defense W81XWH-10-1-02802; NHS: UM1 CA186107, P01 CA87969, R01 CA49449, R01-CA67262, UM1 CA176726; NJO: National Cancer Institute (NIH-K07 CA095666, R01-CA83918, NIH-K22-CA138563, and P30-CA072720) and the Cancer Institute of New Jersey; If Sara Olson and/or Irene Orlow is a co-author, please add NCI CCSG award (P30-CA008748) to the funding sources; NOR: Helse Vest, The Norwegian Cancer Society, The Research Council of Norway; NTH: Radboud University Medical Centre; OPL: National Health and Medical Research Council (NHMRC) of Australia (APP1025142) and Brisbane Women’s Club; ORE: OHSU Foundation; OVA: This work was supported by Canadian Institutes of Health Research grant (MOP-86727) and by NIH/NCI 1 R01CA160669-01A1; PLC: Intramural Research Program of the National Cancer Institute; POC: Pomeranian Medical University; POL: Intramural Research Program of the National Cancer Institute; PVD: Canadian Cancer Society and Cancer Research Society GRePEC Program; RBH: National Health and Medical Research Council of Australia; RMH: Cancer Research UK, Royal Marsden Hospital; RPC: National Institute of Health (P50-CA159981, R01-CA126841); SEA: Cancer Research UK (C490/A10119 C490/A10124); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; SIS: NIH, National Institute of Environmental Health Sciences, Z01-ES044005 and Z01-ES049033; SMC: The bbSwedish Research Council-SIMPLER infrastructure; the Swedish Cancer Foundation; SON: National Health Research and Development Program, Health Canada, grant 6613-1415-53; SRO: Cancer Research UK (C536/A13086, C536/A6689) and Imperial Experimental Cancer Research Centre (C1312/A15589); STA: NIH grants U01 CA71966 and U01 CA69417; SWE: Swedish Cancer foundation, WeCanCureCancer and VårKampMotCancer foundation; SWH: NIH (NCI) grant R37-CA070867; TBO: National Institutes of Health (R01-CA106414-A2), American Cancer Society (CRTG-00-196-01-CCE), Department of Defense (DAMD17-98-1-8659), Celma Mastery Ovarian Cancer Foundation; TOR: NIH grants R01-CA063678 and R01 CA063682; UCI: NIH R01-CA058860 and the Lon V Smith Foundation grant LVS39420; UHN: Princess Margaret Cancer Centre Foundation-Bridge for the Cure; UKO: The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre; UKR: Cancer Research UK (C490/A6187), UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; USC: P01CA17054, P30CA14089, R01CA61132, N01PC67010, R03CA113148, R03CA115195, N01CN025403, and California Cancer Research Program (00-01389V-20170, 2II0200); VAN: BC Cancer Foundation, VGH & UBC Hospital Foundation; VTL: NIH K05-CA154337; WMH: National Health and Medical Research Council of Australia, Enabling Grants ID 310670 & ID 628903. Cancer Institute NSW Grants 12/RIG/1-17 & 15/RIG/1-16; WOC: National Science Centren (N N301 5645 40). The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academia Reserve. The prostate cancer genome-wide association analyses: we pay tribute to Brian Henderson, who was a driving force behind the OncoArray project, for his vision and leadership, and who sadly passed away before seeing its fruition. We also thank the individuals who participated in these studies enabling this work. The ELLIPSE/PRACTICAL (http//:practical.icr.ac.uk) prostate cancer consortium and his collaborating partners were supported by multiple funding mechanisms enabling this current work. ELLIPSE/PRACTICAL Genotyping of the OncoArray was funded by the US National Institutes of Health (NIH) (U19 CA148537 for ELucidating Loci Involved in Prostate Cancer SuscEptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract number HHSN268201200008I). Additional analytical support was provided by NIH NCI U01 CA188392 (F.R.S.). Funding for the iCOGS infrastructure came from the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, and C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112; the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. This work was supported by the Canadian Institutes of Health Research, European Commission’s Seventh Framework Programme grant agreement n° 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, C16913/A6135, C5047/A21332 and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative grant: No. 1 U19 CA148537-01 (the GAME-ON initiative). We also thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), The Orchid Cancer Appeal, The National Cancer Research Network UK, and The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. The Prostate Cancer Program of Cancer Council Victoria also acknowledge grant support from The National Health and Medical Research Council, Australia (126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394, and 614296), VicHealth, Cancer Council Victoria, The Prostate Cancer Foundation of Australia, The Whitten Foundation, PricewaterhouseCoopers, and Tattersall’s. E.A.O., D.M.K., and E.M.K. acknowledge the Intramural Program of the National Human Genome Research Institute for their support. The BPC3 was supported by the U.S. National Institutes of Health, National Cancer Institute (cooperative agreements U01-CA98233 to D.J.H., U01-CA98710 to S.M.G., U01-CA98216 to E.R., and U01-CA98758 to B.E.H., and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics). CAPS GWAS study was supported by the Swedish Cancer Foundation (grant no 09-0677, 11-484, 12-823), the Cancer Risk Prediction Center (CRisP; www.crispcenter.org), a Linneus Centre (Contract ID 70867902) financed by the Swedish Research Council, Swedish Research Council (grant no K2010-70 × -20430-04-3, 2014-2269). The Hannover Prostate Cancer Study was supported by the Lower Saxonian Cancer Society. PEGASUS was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. RAPPER was supported by the NIHR Manchester Biomedical Research Center, Cancer Research UK (C147/A25254, C1094/A18504) and the EU’s 7th Framework Programme Grant/Agreement no 60186. Overall: this research has been conducted using the UK Biobank Resource (application number 16549). NHS is supported by UM1 CA186107 (NHS cohort infrastructure grant), P01 CA87969, and R01 CA49449. NHSII is supported by UM1 CA176726 (NHSII cohort infrastructure grant), and R01-CA67262. A.L.K. is supported by R01 MH107649. We would like to thank the participants and staff of the NHS and NHSII for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.
Published: 2019

18. Analysis of a RECQL splicing mutation, c.1667_1667+3delAGTA, in breast cancer patients and controls from Central Europe

Author: Tjoung-Won Park-Simon, Wulf Siggelkow, Natalia Antonenkova, Peter Hillemanns, Thilo Dörk, Hans Christiansen, Natalia Bogdanova, Katja Pfeifer, and Peter Schürmann
Subjects: Adult, 0301 basic medicine, Oncology, Heterozygote, Cancer Research, medicine.medical_specialty, Republic of Belarus, RNA Splicing, Breast Neoplasms, Biology, Bioinformatics, Risk Assessment, Loss of heterozygosity, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Germany, Internal medicine, Odds Ratio, Genetics, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Clinical significance, Family history, Alleles, Genetics (clinical), Aged, RecQ Helicases, Odds ratio, Middle Aged, medicine.disease, Founder Effect, 030104 developmental biology, Receptors, Estrogen, Case-Control Studies, 030220 oncology & carcinogenesis, Mutation, Mutation (genetic algorithm), Female, Poland, Breast carcinoma
Abstract: RECQL is a DNA helicase required for genomic stability. Two studies have recently identified RECQL as a novel breast cancer susceptibility gene. The most common RECQL mutation, the 4 bp-deletion c.1667_1667+3delAGTA, was five-fold enriched in Polish breast cancer patients, but the exact magnitude of the risk is uncertain. We investigated two hospital-based breast cancer case-control series from Belarus and Germany, respectively, comprising a total of 2596 breast cancer patients and 2132 healthy females. The mutation was found in 9 cases and 6 controls, with an adjusted Odds Ratio 1.23 (95% CI 0.44-3.47; p = 0.69) in the combined analysis. Among the cases, heterozygosity for c.1667_1667+3delAGTA was linked with estrogen-receptor positive breast cancer. There was no significant difference in age at diagnosis between carriers and non-carriers, and only one of the carriers reported a first-degree family history. Meta-analysis with the initial study from Poland suggests an about two-fold increase in risk for this mutation (OR 2.51; 95% CI 1.13-5.57, p = 0.02). Altogether, the data indicate that RECQL* c.1667_1667+3delAGTA is not a high-risk mutation for breast cancer though it could represent a moderate-risk breast cancer susceptibility allele. Further studies will be required to determine the clinical significance of testing for this RECQL mutation.
Published: 2016

19. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology

Author: Peter Hillemanns, Ralf Bützow, Joseph H. Rothstein, Jennifer A. Doherty, Celeste Leigh Pearce, Louise A. Brinton, Sandra Orsulic, Lene Lundvall, Susanne K. Kjaer, Irene Orlow, Marc T. Goodman, Diether Lambrechts, Agnieszka Podgorska, Kathryn L. Terry, Yukie Bean, Joseph L. Kelley, Jonathan Tyrer, Svend Aage Engelholm, Linda S. Cook, John R. McLaughlin, Melissa Kellar, Graham G. Giles, Shashikant Lele, Anne M. van Altena, Tanja Pejovic, Lotte Nedergaard, Edwin S. Iversen, Robert P. Edwards, Ingvild L. Tangen, Andreas du Bois, Rosalind Glasspool, Florian Heitz, Beth Y. Karlan, Peter A. Fasching, Liisa M. Pelttari, Aleksandra Gentry-Maharaj, Argyrios Ziogas, Pamela J. Thompson, Jenny Chang-Claude, Camilla Krakstad, Andrew Berchuck, Simon A. Gayther, Alice S. Whittemore, Kunle Odunsi, Liv Cecilie Vestrheim Thomsen, Jolanta Kupryjanczyk, Leon F.A.G. Massuger, Nicolas Wentzensen, Karen H. Lu, Alexander Hein, Steven A. Narod, Harvey A. Risch, Francesmary Modugno, Fiona Bruinsma, Joanna Plisiecka-Halasa, Julie M. Cunningham, Sara H. Olson, Linda E. Kelemen, Xifeng Wu, Robert A. Vierkant, Daniel W. Cramer, Yurii B. Shvetsov, Elisa V. Bandera, Arif B. Ekici, Heli Nevanlinna, Lynne R. Wilkens, Jolanta Lissowska, Melissa C. Southey, Shelley S. Tworoger, Allan Jensen, Christine Walsh, Usha Menon, Line Bjørge, Iain A. McNeish, Katja K.H. Aben, Dong Liang, Joellen M. Schildkraut, Ellen L. Goode, Els Van Nieuwenhuysen, Ignace Vergote, Brooke L. Fridley, Weiva Sieh, Anna H. Wu, Thomas A. Sellers, Nhu D. Le, Jacek Gronwald, Anna Jakubowska, Paul D.P. Pharoah, Mary Anne Rossing, Thilo Dörk, Natalia Antonenkova, Lambertus A. Kiemeney, Douglas A. Levine, Cezary Cybulski, Diana Eccles, Hoda Anton-Culver, Matthias W. Beckmann, Valerie McGuire, Elizabeth M. Poole, Claus Høgdall, Ed Dicks, Honglin Song, Sandrina Lambrechts, Ian G. Campbell, Michelle A.T. Hildebrandt, Madalene Earp, Roberta B. Ness, James Paul, Jan Lubinski, Natalia Bogdanova, Estrid Høgdall, Alice W. Lee, Malcolm C. Pike, Ira Schwaab, Nadeem Siddiqui, Włodzimierz Sawicki, Kirsten B. Moysich, Philipp Harter, Angela Brooks-Wilson, Ingo B. Runnebaum, Karen Carty, Rikki Cannioto, Susan J. Ramus, Georgia Chenevix-Trench, Catherine M. Phelan, Sabine Behrens, Jenny Lester, Department of Pathology, Medicum, Clinicum, Department of Obstetrics and Gynecology, Kelemen, Linda E [0000-0003-4362-9784], Hein, Alexander [0000-0003-2601-3398], Behrens, Sabine [0000-0002-9714-104X], Hillemanns, Peter [0000-0001-9829-3531], Nevanlinna, Heli [0000-0002-0916-2976], Kjaer, Susanne K [0000-0002-8347-1398], Jensen, Allan [0000-0001-8124-4880], Cunningham, Julie M [0000-0002-8159-3025], Vierkant, Robert A [0000-0001-6242-5221], Bjorge, Line [0000-0002-0240-2770], Gronwald, Jacek [0000-0002-3643-2871], Brinton, Louise A [0000-0003-3853-8562], Pharoah, Paul DP [0000-0001-8494-732X], Tyrer, Jonathan P [0000-0003-3724-4757], McNeish, Iain [0000-0002-9387-7586], Eccles, Diana [0000-0002-9935-3169], Menon, Usha [0000-0003-3708-1732], Ramus, Susan J [0000-0003-0005-7798], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, Ovarian Cancer Association Consortium, consortia, Thymidylate synthase, Ovarian neoplasms, lcsh:Chemistry, 0302 clinical medicine, expression quantitative trait locus, Consortia, Ovarian carcinoma, Odds Ratio, genetics, Expression quantitative trait locus, lcsh:QH301-705.5, Spectroscopy, Single-nucleotide polymorphism, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], biology, GENETIC-VARIATION, General Medicine, Middle Aged, ovarian neoplasms, single-nucleotide polymorphism, Adenocarcinoma, Mucinous, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Computer Science Applications, Gene Expression Regulation, Neoplastic, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Adenocarcinoma, Female, DIFFERENT HISTOTYPES, Signal Transduction, Australian Ovarian Cancer Study Group, Risk, EXPRESSION, medicine.medical_specialty, SUSCEPTIBILITY LOCI, 0699 Other Biological Sciences, Quantitative Trait Loci, 3122 Cancers, thymidylate synthase, Polymorphism, Single Nucleotide, Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, Internal medicine, 0399 Other Chemical Sciences, medicine, Genetics, CANCER ASSOCIATION CONSORTIUM, Humans, RNA, Antisense, ddc:610, Physical and Theoretical Chemistry, Allele, Molecular Biology, Genetic Association Studies, Hydro-Lyases, METAANALYSIS, 0604 Genetics, Chemical Physics, Organic Chemistry, gynecology, Case-control study, Proteins, Odds ratio, medicine.disease, SYNTHASE MESSENGER-RNA, 030104 developmental biology, Logistic Models, CARBON TRANSFER PATHWAY, lcsh:Biology (General), lcsh:QD1-999, Enolase superfamily member 1, Gynecology, enolase superfamily member 1, Case-Control Studies, Expression quantitative trait loci, biology.protein, 1182 Biochemistry, cell and molecular biology, CIGARETTE-SMOKING, Other Biological Sciences, Other Chemical Sciences
Abstract: Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3′ gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09, 95% CI = 0.97–1.22, p = 0.15, N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13, 95% CI = 1.03–1.24, p = 0.01, N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10−28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
Published: 2018

20. Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility

Author: Andreas du Bois, Douglas F. Easton, Aleksandra Gentry-Maharaj, Heli Nevanlinna, Fiona Bruinsma, Iwona K. Rzepecka, Anna H. Wu, Jenny Chang-Claude, Jolanta Lissowska, Natalia Antonenkova, Beata Spiewankiewicz, Christine Walsh, Louise A. Brinton, Xifeng Wu, Leon F.A.G. Massuger, Audrey Y. Jung, Nadeem Siddiqui, Jenny Lester, Evelyn Despierre, Rosalind Glasspool, Jacek Gronwald, Claus Høgdall, Ellen L. Goode, Liisa M. Pelttari, Edwin S. Iversen, Alice S. Whittemore, Lynne R. Wilkens, Lene Lundvall, Robert P. Edwards, Natalia Bogdanova, Camilla Krakstad, Kunle Odunsi, Diana Eccles, Katja K.H. Aben, Weiva Sieh, Diether Lambrechts, Simon A. Gayther, Thomas A. Sellers, Satoyo Hosono, Yin Ling Woo, Jolanta Kupryjanczyk, Matthias W. Beckmann, Bu-Tian Ji, Shashi Lele, Pamela J. Thompson, Nicolas Wentzensen, Kirsten B. Moysich, Alice W. Lee, Kathryn L. Terry, Ira Schwaab, Estrid Høgdall, Yurii B. Shvetsov, Francesmary Modugno, Liv Cecilie Vestrheim Thomsen, Elizabeth M. Poole, Xiao-Ou Shu, Michelle A.T. Hildebrandt, Joellen M. Schildkraut, Arif B. Ekici, Hoda Anton-Culver, Philipp Harter, Celeste Leigh Pearce, Kristine G. Wicklund, Georgia Chenevix-Trench, Ralf Bützow, Eva S. Schernhammer, Madalene Earp, Roberta B. Ness, Steven A. Narod, James Paul, Tanja Pejovic, Soo-Hwang Teo, Florian Heitz, Catherine M. Phelan, Stacey J. Winham, Beth Y. Karlan, Susanne K. Kjaer, Sandrina Lambrechts, Jan Lubinski, Irene Orlow, Peter A. Fasching, Valerie McGuire, Lotte Ansgaard Thomsen, Joseph H. Rothstein, Honglin Song, Melissa Kellar, Usha Menon, Alvaro N.A. Monteiro, Ian G. Campbell, Hannah P. Yang, Graham G. Giles, Harvey A. Risch, Shan Wang-Gohrke, Linda E. Kelemen, Andrew Berchuck, Dong Liang, Karen Lu, Elisa V. Bandera, Robert A. Vierkant, John R. McLaughlin, Peter Hillemanns, Alexander Hein, Julie M. Cunningham, Daniel W. Cramer, Yukie Bean, Clareann H. Bunker, Brooke L. Fridley, Jennifer A. Doherty, Mary Anne Rossing, Joe Dennis, Shelley S. Tworoger, Allan Jensen, Thilo Dörk, Douglas A. Levine, Wei Zheng, Yong-Bing Xiang, Matthias Dürst, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, Keitaro Matsuo, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Lara E. Sucheston-Campbell, Boon Kiong Lim, Sara H. Olson, Angela Brooks-Wilson, Ingo B. Runnebaum, Zheng Li, Jenny B. Permuth, Roger L. Milne, Barry P. Rosen, Iain A. McNeish, Argyrios Ziogas, Hui Yi Lin, Sandra Orsulic, Nhu D. Le, Malcolm C. Pike, Linda S. Cook, Line Bjørge, Karen Carty, Cezary Cybulski, Ganna Chornokur, Jonathan Tyrer, Susan J. Ramus, Anne M. van Altena, Marc T. Goodman, Ignace Vergote, Ingvild L. Tangen, Department of Pathology, Clinicum, University of Helsinki, Department of Obstetrics and Gynecology, Medicum, Doctoral Programme in Biomedicine, Scott, Rodney John, Dennis, Joe [0000-0003-4591-1214], Bruinsma, Fiona [0000-0002-9356-2015], Cunningham, Julie M [0000-0002-8159-3025], Giles, Graham G [0000-0003-4946-9099], Jakubowska, Anna [0000-0002-5650-0501], Li, Zheng [0000-0002-6141-4990], Sellers, Thomas A [0000-0002-7832-0405], Pharoah, Paul DP [0000-0001-8494-732X], Goode, Ellen L [0000-0002-9094-8326], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, endocrine system diseases, Hydrolases, Cell Membranes, Gene Expression, A Kinase Anchor Proteins, lcsh:Medicine, Genome-wide association study, GTPase, Carcinoma, Ovarian Epithelial, Biochemistry, Signaling Molecules, Cell Signaling, Risk Factors, 3123 Gynaecology and paediatrics, Medizinische Fakultät, GTPase Gene, Medicine and Health Sciences, Guanine Nucleotide Exchange Factors, Small GTPase, lcsh:Science, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Multidisciplinary, Invasive Tumors, Genomics, A Kinase Anchor Proteins/genetics, Polymorphism, Single Nucleotide/genetics, female genital diseases and pregnancy complications, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Enzymes, Multidisciplinary Sciences, Carcinoma, Ovarian Epithelial/genetics, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Science & Technology - Other Topics, Female, Guanine nucleotide exchange factor, Cellular Structures and Organelles, Anatomy, TRAITS, Research Article, Signal Transduction, Histology, Genotype, CARCINOMA, General Science & Technology, Rho GTPase-Activating Protein 5, Quantitative Trait Loci, 3122 Cancers, Ras Signaling, Biology, Polymorphism, Single Nucleotide, Monomeric GTP-Binding Proteins/genetics, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, GTP-binding protein regulators, MD Multidisciplinary, Genome-Wide Association Studies, Genetics, Humans, Gene Regulation, Genetic Predisposition to Disease, ddc:610, GENOME-WIDE ASSOCIATION, Rho Guanine Nucleotide Exchange Factors/genetics, Genetic Association Studies, Monomeric GTP-Binding Proteins, Science & Technology, lcsh:R, Biology and Life Sciences, Proteins, Membrane Proteins, Computational Biology, Cancers and Neoplasms, Human Genetics, Cell Biology, Genome Analysis, SUPER-ENHANCERS, Guanosine Triphosphatase, 030104 developmental biology, Cancer research, Enzymology, lcsh:Q, 3111 Biomedicine, Ras superfamily, Quantitative Trait Loci/genetics, Rho Guanine Nucleotide Exchange Factors
Abstract: Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations. ispartof: PLOS ONE vol:13 issue:7 ispartof: location:United States status: published
Published: 2018

21. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

Author: Ellen L. Goode, Andreas du Bois, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Joe Dennis, Celeste Leigh Pearce, Kristine G. Wicklund, Lynne R. Wilkens, Rosalind Glasspool, Diana Eccles, Susanne K. Kjaer, Roberta B. Ness, James Paul, Matthias Dürst, Camilla Krakstad, Irene Orlow, Rachel Palmieri Weber, Jonathan Tyrer, Valerie McGuire, Matthias W. Beckmann, Thomas A. Sellers, Elizabeth M. Poole, Ian G. Campbell, Arif B. Ekici, Steven A. Narod, Lotte Nedergaard, Shan Wang-Gohrke, Estrid Høgdall, Yurii B. Shvetsov, Douglas F. Easton, Sandrina Lambrechts, Linda E. Kelemen, Zhihua Chen, Karen Lu, Elisa V. Bandera, Qiyuan Li, Joellen M. Schildkraut, Agnieszka Dansonka-Mieszkowska, Liisa M. Pelttari, Kate Lawrenson, Sandra Orsulic, Ed Dicks, Kirsten B. Moysich, Melissa C. Southey, Christine Walsh, Louise A. Brinton, Argyrios Ziogas, Yukie Bean, Julie M. Cunningham, Patricia Harrington, Philipp Harter, Sara H. Olson, Keitaro Matsuo, Alvaro N.A. Monteiro, Claus Høgdall, Anne M. van Altena, Jenny Lester, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Yu-Tang Gao, Shelley S. Tworoger, Maria Bisogna, Michelle A.T. Hildebrandt, Yian Ann Chen, Iain A. McNeish, Allan Jensen, Diether Lambrechts, Usha Menon, Satoyo Hosono, Pamela J. Thompson, Yin Ling Woo, Jennifer Permuth-Wey, Francesmary Modugno, Matthew L. Freedman, Linda S. Cook, Harvey A. Risch, Ya-Yu Tsai, Marc T. Goodman, Dong Liang, Kathryn L. Terry, Soo Hwang Teo, Lara E. Sucheston-Campbell, Ira Schwaab, Robert A. Vierkant, Georgia Chenevix-Trench, Ralf Bützow, Siddhartha Kar, Wei Zheng, Nhu D. Le, Andrew Berchuck, Brooke L. Fridley, Edwin S. Iversen, Robert P. Edwards, Peter Hillemanns, Daniel W. Cramer, Mary Anne Rossing, Thilo Dörk, Malcolm C. Pike, Jolanta Kupryjanczyk, Anja Rudolph, Joseph H. Rothstein, Douglas A. Levine, Xiao-Ou Shu, Nicolas Wentzensen, Hannah P. Yang, Graham G. Giles, Hoda Anton-Culver, Line Bjørge, Peter A. Fasching, Catherine M. Phelan, Simon A. Gayther, Ignace Vergote, Alexander Hein, Cezary Cybulski, Ingvild L. Tangen, Els Van Nieuwenhuysen, Joseph L. Kelley, Honglin Song, Helen Baker, Alice S. Whittemore, Melissa Kellar, Kunle Odunsi, Bu Tian Ji, Heli Nevanlinna, Jolanta Lissowska, Shashi Lele, Barry P. Rosen, Katja K.H. Aben, Karen Carty, Leon F.A.G. Massuger, Iwona K. Rzepecka, Susan J. Ramus, Angela Brooks-Wilson, Xifeng Wu, Ingo B. Runnebaum, Lene Lundvall, Natalia Bogdanova, Helga B. Salvesen, Alice W. Lee, Jan Lubinski, Agnieszka Timorek, Nadeem Siddiqui, Anna H. Wu, Natalia Antonenkova, Weiva Sieh, Tanja Pejovic, John R. McLaughlin, Arto Leminen, Jennifer A. Doherty, Florian Heitz, Beth Y. Karlan, and Jacek Grownwald
Subjects: endocrine system diseases, Microarray, Epidemiology, Genome-wide association study, Global Health, Bioinformatics, Medical and Health Sciences, Risk Factors, 2.1 Biological and endogenous factors, Aetiology, Hox gene, Cancer, Ovarian Neoplasms, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Nuclear Proteins, DNA, Neoplasm, female genital diseases and pregnancy complications, Ovarian Cancer, Gene Expression Regulation, Neoplastic, Serous fluid, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Biotechnology, Australian Ovarian Cancer Study Group, Genotype, Population, Cystadenocarcinoma, Single-nucleotide polymorphism, Computational biology, Biology, Article, Rare Diseases, Australian Cancer Study, Genetics, Humans, Genetic Predisposition to Disease, education, Gene, Genetic association, Neoplastic, Prevention, Human Genome, Serous, DNA, Cystadenocarcinoma, Serous, Gene Expression Regulation, Neoplasm, Morbidity, Transcription Factors, Genome-Wide Association Study
Abstract: Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.
Published: 2015

22. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

Author: Alice S. Whittemore, Kunle Odunsi, Joe Dennis, Usha Menon, Agnieszka Dansonka-Mieszkowska, Angela Brooks-Wilson, Ingo B. Runnebaum, Melissa C. Southey, Bu-Tian Ji, Y. Ann Chen, Shashi Lele, Dong Liang, Jacek Gronwald, Keitaro Matsuo, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Andreas du Bois, Diether Lambrechts, Simon A. Gayther, Aleksandra Gentry-Maharaj, Brooke L. Fridley, Boon Kiong Lim, Kathryn L. Terry, Ira Schwaab, Jenny Chang-Claude, Mary Anne Rossing, Thilo Dörk, Kirsten B. Moysich, Satoyo Hosono, Rosalind Glasspool, Camilla Krakstad, Thomas A. Sellers, Douglas A. Levine, Estrid Høgdall, Yurii B. Shvetsov, Joellen M. Schildkraut, Douglas F. Easton, Philipp Harter, Francesmary Modugno, Ellen L. Goode, Karen Carty, John R. McLaughlin, Celeste Leigh Pearce, Alvaro N.A. Monteiro, Yu-Tang Gao, Arto Leminen, Peter A. Fasching, Kristine G. Wicklund, Maria Bisogna, Linda E. Kelemen, Sandrina Lambrechts, Edwin S. Iversen, Jennifer A. Doherty, Karen Lu, Robert P. Edwards, Elisa V. Bandera, Christine Walsh, Liisa M. Pelttari, Fiona Bruinsma, Iwona K. Rzepecka, Michelle A.T. Hildebrandt, Argyrios Ziogas, Soo-Hwang Teo, Susanne K. Kjaer, Lara E. Sucheston-Campbell, Nadeem Siddiqui, Hui-Yi Lin, Linda S. Cook, Julie M. Cunningham, Louise A. Brinton, Shelley S. Tworoger, Allan Jensen, Irene Orlow, Natalia Bogdanova, Helga B. Salvesen, Ralf Bützow, Steven A. Narod, Susan J. Ramus, Xifeng Wu, Anja Rudolph, Jolanta Kupryjanczyk, Nicolas Wentzensen, Clareann H. Bunker, Ganna Chornokur, Ed Dicks, Joseph H. Rothstein, Wei Zheng, Andrew Berchuck, Ignace Vergote, Lynne R. Wilkens, Ingvild L. Tangen, Beata Spiewankiewicz, Alice W. Lee, Yukie Bean, Peter Hillemanns, Lotte Ansgaard Thomsen, Leon F.A.G. Massuger, Valerie McGuire, Diana Eccles, Catherine M. Phelan, Yin Ling Woo, Patricia Harrington, Rachel Palmieri Weber, Evelyn Despierre, Hoda Anton-Culver, Anne M. van Altena, Eva S. Schernhammer, Ernest K. Amankwah, Ian G. Campbell, Jonathan Tyrer, Daniel W. Cramer, Matthias W. Beckmann, Shan Wang-Gohrke, Hannah P. Yang, Graham G. Giles, Lene Lundvall, Ian McNeish, Claus Høgdall, Elizabeth M. Poole, Roger L. Milne, Honglin Song, Hanis Nazihah Hasmad, Jan Lubinski, Ursula Eilber, Jenny Lester, Arif B. Ekici, Pamela J. Thompson, Harvey A. Risch, Kate Lawrenson, Malcolm C. Pike, Jennifer Permuth-Wey, Sandra Orsulic, Roberta B. Ness, James Paul, Robert A. Vierkant, Alexander Hein, Line Bjørge, Zhihua Chen, Marc T. Goodman, Melissa Kellar, Cezary Cybulski, Xiao-Ou Shu, Matthias Dürst, Barry P. Rosen, Heather S.L. Jim, Anna H. Wu, Natalia Antonenkova, Weiva Sieh, Tanja Pejovic, Florian Heitz, Beth Y. Karlan, Nhu D. Le, Heli Nevanlinna, Sara H. Olson, Jolanta Lissowska, and Katja K.H. Aben
Subjects: Oncology, medicine.medical_specialty, education.field_of_study, Epidemiology, Population, Single-nucleotide polymorphism, Genome-wide association study, Odds ratio, Biology, medicine.disease, Bioinformatics, Internal medicine, medicine, Carcinoma, Epithelial–mesenchymal transition, Ovarian cancer, Lung cancer, education, Genetics (clinical)
Abstract: Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value
Published: 2015

23. Genome-wide significant risk associations for mucinous ovarian carcinoma

Author: Jenny Lester, Arif B. Ekici, Xiao-Ou Shu, Georgia Chenevix-Trench, Julie M. Cunningham, Catherine M. Phelan, Tassja J. Spindler, Shelley S. Tworoger, Allan Jensen, Diana Eccles, Wei Zheng, Satoyo Hosono, Svend Aage Engelholm, Linda S. Cook, Thomas A. Sellers, John R. McLaughlin, Matthias W. Beckmann, Elizabeth M. Poole, Ignace Vergote, Francesmary Modugno, Jennifer A. Doherty, Sandrina Lambrechts, Lara Sucheston, Wang Gohrke Shan, Rosalind Glasspool, Barry P. Rosen, Pamela J. Thompson, Christine Walsh, Camilla Krakstad, Jennifer Permuth-Wey, Hoda Anton-Culver, Ralf Bützow, Ed Dicks, Yin Ling Woo, Honglin Song, Qiyuan Li, Leon F.A.G. Massuger, Yurii B. Shvetsov, Joellen M. Schildkraut, Xiaoqing Chen, Hannah P. Yang, Graham G. Giles, Sara H. Olson, Edwin S. Iversen, Claus Høgdall, Jacek Grownwald, Fiona Bruinsma, Peter Hillemanns, Iwona K. Rzepecka, Douglas T. Easton, Robert P. Edwards, Lynne R. Wilkens, Yukie Bean, Y. Ann Chen, Jonathan Tyrer, Tanja Pejovic, Patricia Harrington, Iain A. McNeish, Steven A. Narod, Joanna Moes-Sosnowska, Hanis Nazihah Hasmad, Ji-Heui Seo, Line Bjørge, Peter A. Fasching, Daniel W. Cramer, Florian Heitz, Beth Y. Karlan, Cezary Cybulski, Simon A. Gayther, Jolanta Kupryjanczyk, Nhu D. Le, Alexander Hein, Soo Hwang Teo, Nicolas Wentzensen, Valerie McGuire, Michelle A.T. Hildebrandt, Argyrios Ziogas, Heli Nevanlinna, Karen H. Lu, Diether Lambrechts, Kirsten B. Moysich, Jonathan Beesley, Kate Lawrenson, Ian G. Campbell, Andrew Berchuck, Philipp Harter, Lene Lundvall, Sandra Orsulic, Kathryn L. Terry, Jolanta Lissowska, Helen Baker, Matthew L. Freedman, Linda E. Kelemen, Maria Bisogna, Celeste Leigh Pearce, Ira Schwaab, Elisa V. Bandera, Kristine G. Wicklund, Arto Leminen, Nadeem Siddiqui, Joseph H. Rothstein, Melissa Kellar, Matthias Dürst, Harvey A. Risch, Włodzimierz Sawicki, Katja K.H. Aben, Alice S. Whittemore, Kunle Odunsi, Shashi Lele, Noor Azmi Mat Adenan, Susanne K. Kjaer, Robert A. Vierkant, Jan Lubinski, Natalia Bogdanova, Helga B. Salvesen, Anja Rudolph, Els Van Nieuwenhuysen, Irene Orlow, Joe Dennis, Ingvild L. Tangen, Estrid Høgdall, Alice W. Lee, Roberta B. Ness, James Paul, Malcolm C. Pike, Rachel Palmieri Weber, Anna H. Wu, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, Natalia Antonenkova, Anne M. van Altena, Xifeng Wu, Keitaro Matsuo, Anna Jakubowska, Paul D.P. Pharoah, Weiva Sieh, Lambertus A. Kiemeney, Lotte Nedergaard, Ursula Eilber, Janet M. Lee, Zhihua Chen, Andreas du Bois, Joseph L. Kelley, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Ellen L. Goode, Bu Tian Ji, Liisa M. Pelttari, Usha Menon, Dong Liang, Yu-Tang Gao, Brooke L. Fridley, Mary Anne Rossing, Thilo Dörk, Douglas A. Levine, Louise A. Brinton, Marc T. Goodman, Angela Brooks-Wilson, Ingo B. Runnebaum, Karen Carty, and Susan J. Ramus
Subjects: Green Fluorescent Proteins, Molecular Sequence Data, Quantitative Trait Loci, Single-nucleotide polymorphism, Genome-wide association study, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Cell Line, Tumor, Ovarian carcinoma, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Association Studies, 030304 developmental biology, Genetic association, Cell Nucleus, Homeodomain Proteins, Ovarian Neoplasms, 0303 health sciences, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, medicine.disease, Adenocarcinoma, Mucinous, Neoplasm Proteins, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Gene Expression Regulation, Neoplastic, Microscopy, Fluorescence, Chromosomes, Human, Pair 2, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Expression quantitative trait loci, Cancer research, Adenocarcinoma, Female, Ovarian cancer, Genome-Wide Association Study
Abstract: Genome-wide association studies have identified several risk associations for ovarian carcinomas (OC) but not for mucinous ovarian carcinomas (MOC). Genotypes from OC cases and controls were imputed into the 1000 Genomes Project reference panel. Analysis of 1,644 MOC cases and 21,693 controls identified three novel risk associations: rs752590 at 2q13 (P = 3.3 × 10−8), rs711830 at 2q31.1 (P = 7.5 × 10−12) and rs688187 at 19q13.2 (P = 6.8 × 10−13). Expression Quantitative Trait Locus (eQTL) analysis in ovarian and colorectal tumors (which are histologically similar to MOC) identified significant eQTL associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10−4, FDR = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors, and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.
Published: 2015

24. PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1

Author: Qin Wang, kConFab, Paolo Radice, Tao Liu, Isabel dos-Santos-Silva, Douglas F. Easton, Joe Dennis, Qi Guo, Michael Lush, Jessada Thutkawkorapin, Diether Lambrechts, Barbara Kremeyer, Fergus J. Couch, Pascal Guénel, Melanie Gündert, Rita K. Schmutzler, William J. Blot, Julian Peto, Christine B. Ambrosone, Wei Zheng, Mikael Eriksson, Ute Hamann, Johanna Rantala, Barbara Burwinkel, Michael J. Kerin, Johanna Lundin, Graham G. Giles, Hiltrud Brauch, Hoda Anton-Culver, Veli-Matti Kosma, Marjanka K. Schmidt, Aocs Investigators, Paula Maguire, Marike Gabrielson, Judith S. Brand, Simone Picelli, Rajeshwari Marikkannu, Quan Du, Irene L. Andrulis, Valerie Rhenius, Kyriaki Michailidou, Susan L. Neuhausen, Vinaykumar Kontham, Alison M. Dunning, Hermann Brenner, Thilo Dörk, Elinor J. Sawyer, Christopher A. Haiman, Anna González-Neira, Thérèse Truong, Peter Devilee, Qiuyin Cai, Susanna von Holst, Peter A. Fasching, Anna Marie Mulligan, Bernardo Bonanni, Javier Benítez, Kamila Czene, Loic Le Marchand, Katri Pylkäs, Henrik Flyger, Jacques Simard, Manjeet K. Bolla, Alfons Meindl, Per Hall, Simon S. Cross, Annika Lindblom, Emily Hallberg, Christos Aravidis, Sara Margolin, Vessela N. Kristensen, Carl Blomqvist, Annegien Broeks, John W.M. Martens, Jonine D. Figueroa, Xiang Jiao, Montserrat Garcia-Closas, Mitul Shah, Matthias W. Beckmann, Thomas Brüning, Guanmengqian Huang, John L. Hopper, Jan Lubinski, Michael Jones, Anthony J. Swerdlow, Roger L. Milne, Patricia Harrington, Caroline Seynaeve, Arto Mannermaa, Liping Luo, Natalia Antonenkova, Tatjana Adamovic, Angela Cox, Maartje J. Hooning, Volker Arndt, Dieter Flesch-Janys, Camilla Wendt, Stig E. Bojesen, Melissa C. Southey, Robert Winqvist, Anna Jakubowska, Paul D.P. Pharoah, Bram Boeckx, Sandra Deming-Halverson, Heli Nevanlinna, Jenny Chang-Claude, School of Medicine / Clinical Medicine, Cardiology, Medical Oncology, Department of Oncology, Clinicum, University of Helsinki, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, and HUS Comprehensive Cancer Center
Subjects: EXPRESSION, 0301 basic medicine, Cellbiologi, 3122 Cancers, DNA-SEQUENCING DATA, Locus (genetics), Single-nucleotide polymorphism, Biology, Genome, FAMILIES, risk haplotype, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, 3123 Gynaecology and paediatrics, Genetic linkage, Journal Article, medicine, linkage analysis, Allele, Gene, WIDE LINKAGE SCAN, Genetics, Cancer och onkologi, MUTATIONS, familial breast cancer, Haplotype, LOCALIZATION, ASSOCIATION, sequencing, Cell Biology, medicine.disease, GENE, 3. Good health, GENOME, 030104 developmental biology, Oncology, DISCOVERY, Cancer and Oncology, 030220 oncology & carcinogenesis, Priority Research Paper
Abstract: Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD >2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene., published version, peerReviewed
Published: 2017

25. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author: Eitan Friedman, Mattias Van Heetvelde, Jennifer B. Permuth, Joseph Vijai, Patricia A. Ganz, Jennifer A. Doherty, Argyrios Ziogas, Bernard Peissel, Edwin S. Iversen, Angela Brooks-Wilson, Ingo B. Runnebaum, Amanda B. Spurdle, Heli Nevanlinna, Kenneth Offit, Laura Papi, Georgia Chenevix-Trench, Saundra S. Buys, Martin Köbel, Fabienne Lesueur, Elizabeth W. Pugh, Joe Dennis, Sylvie Mazoyer, Diana Eccles, Shirley Hodgson, Jolanta Lissowska, Judy Garber, Pascal Pujol, Kristin K. Zorn, Orland Diez, Marcia Adams, Thomas Conner, Renée T. Fortner, Tjoung-Won Park-Simon, Vanesa García-Barberán, Kerstin Rhiem, Norbert Arnold, Karoline Kuchenbaecker, Susan M. Domchek, María Josefa Mosteiro García, Matthias W. Beckmann, Alex Henderson, Melissa C. Larson, Jane Romm, Anja Rudolph, Steven A. Narod, Mats Jernetz, Jolanta Kupryjanczyk, Natalia Bogdanova, Jacob Musinsky, Helga B. Salvesen, Jonathan Beesley, Paolo Peterlongo, Arif B. Ekici, Clarice R. Weinberg, Marion Piedmonte, Christian F. Singer, Robert L. Nussbaum, Katja K.H. Aben, Michael J. Birrer, Juul T. Wijnen, Elizabeth M. Poole, Phuong L. Mai, David J. Hunter, Tanja Pejovic, Athanassios Vratimos, Barbara Wappenschmidt, Nicolas Wentzensen, Marcus Q. Bernardini, Leigha Senter, Terence Cescon, Daniel W. Cramer, Silvia Tognazzo, Drakoulis Yannoukakos, Jacopo Azzollini, Ignace Vergote, Karen H. Lu, Gustavo C. Rodriguez, Julian Adlard, Tomasz Huzarski, Mark H. Greene, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Paulo C Lyra, Usha Menon, Ralf Bützow, Siddhartha Kar, Manuel R. Teixeira, Conxi Lázaro, Agnieszka Dansonka-Mieszkowska, Aleksandra Gentry-Maharaj, Zsofia K. Stadler, Melissa C. Southey, Ramunas Janavicius, Douglas F. Easton, Digna R. Velez Edwards, Jocelyne Chiquette, Karin Kast, Jonathan Tyrer, Georg Pfeiler, Tara M. Friebel, Bruno Buecher, Goska Leslie, Jackie Cook, Catherine M. Phelan, Steve Ellis, Estrid Høgdall, Beth Y. Karlan, Anthony J. Swerdlow, Sarah E. Ferguson, Rosalind Glasspool, Frans B. L. Hogervorst, Lotte Nedergaard, Britton Trabert, Jack A. Taylor, Irene L. Andrulis, Paolo Radice, Dennis J. Hazelett, Mads Thomassen, Dong Liang, Joseph H. Rothstein, Loren Lipworth, Melissa A. Merritt, Ana Vega, Petra H.M. Peeters, Claus Høgdall, Anna M. Piskorz, Bernardo Bonanni, Janet M. Lee, Malcolm C. Pike, Clemens Liebrich, Zachary C. Fogarty, Bent Ejlertsen, Yuan Chun Ding, Dieter Niederacher, Michael E. Carney, Dominique Stoppa-Lyonnet, Nadine Tung, Curtis Olswold, Ana Osorio, Fiona Bruinsma, Christine Walsh, Fabienne Prieur, Lara E. Sucheston-Campbell, Stephen B. Gruber, Maartje J. Hooning, George Fountzilas, Amanda Black, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Angela R. Bradbury, Helene Holland, Ruth C. Travis, Susana Banerjee, Penelope M. Webb, Brooke L. Fridley, Clara Bodelon, Mary Anne Rossing, Yen Y. Tan, Rosa B. Barkardottir, Jong Won Lee, Stephen J. Chanock, Bruce Poppe, Sandra Fert Ferrer, Melissa Moffitt, Taymaa May, Gustavo Mendoza-Fandiño, Christopher A. Haiman, Alicia Beeghly-Fadiel, Rebecca Sutphen, Michelle A.T. Hildebrandt, Lambertus A. Kiemeney, Thilo Dörk, Douglas A. Levine, Gerasimos Aravantinos, Celeste Leigh Pearce, Sue K. Park, David Van Den Berg, Louise Izatt, Hannah P. Yang, Graham G. Giles, Linda S. Cook, John R. McLaughlin, Nick Orr, Weiva Sieh, Raymonda Varon-Mateeva, Marco Montagna, Honglin Song, Laura Ottini, Ruea-Yea Huang, Joanna Moes-Sosnowska, Anders Bojesen, David M. O'Malley, Andrew K. Godwin, Lucy Side, Sung-Won Kim, Lukasz Szafron, Christoph Engel, Harvey A. Risch, Alexander Hein, Penny Soucy, Elza Khusnutdinova, Ana Peixoto, Arto Leminen, Cora M. Aalfs, Matthias Dürst, Mary B. Daly, Patricia Rice, Nadeem Siddiqui, Dale P. Sandler, Ava Kwong, Madalene Earp, Marjorie J. Riggan, Inge Søkilde Pedersen, Susanne K. Kjaer, Mercedes Durán, Joellen M. Schildkraut, James D. Brenton, D. Gareth Evans, Liisa M. Pelttari, Kimberly F. Doheny, Karen Hosking, Miquel Angel Pujana, Salina B. Chan, Joan Brunet, Trinidad Caldés, Rosemarie Davidson, Jessica N. McAlpine, Jenny Lester, Niclas Håkansson, Kai-ren Ong, Ros Eeles, Francesmary Modugno, Martin Gore, Loic Le Marchand, Robert A. Vierkant, Wendy K. Chung, Christopher I. Amos, N. Charlotte Onland-Moret, Brita Arver, Marc Tischkowitz, Craig Luccarini, Daniel Barrowdale, Laima Tihomirova, Louise A. Brinton, Fergus J. Couch, Alfons Meindl, Nerea Larrañaga, Cristina Rodríguez-Antona, Alice S. Whittemore, Johanna I. Kiiski, Todd L. Edwards, Eric Hahnen, Grzegorz Sukiennicki, Els Van Nieuwenhuysen, Elizabeth J. van Rensburg, Michael Jones, Åke Borg, Edith Olah, Ute Hamann, Liv Cecilie Vestrheim Thomsen, Xiaoqing Chen, Ganna Chornokur, Minouk J. Schoemaker, Marc T. Goodman, Fanny Dao, Andrea Gehrig, Hagay Sobol, Nhu D. Le, Esther M. John, Adriaan Vanderstichele, Antonia Trichopoulou, Kunle Odunsi, Yukie Bean, David G. Huntsman, Lidia Pezzani, V. Wendy Setiawan, Marinus J. Blok, Yael Laitman, Mary Porteous, Patricia Harrington, Samantha Poblete, Shashikant Lele, Anne M. van Altena, Mingajeva Elvira, Lene Lundvall, Dominique Leroux, Annemarie H. van der Hout, Darya Prokofyeva, Debra Frost, Yoke-Eng Chiew, Gad Rennert, Stacey J. Winham, Muy-Kheng Tea, Kirsten B. Moysich, Angel Izquierdo, Anna H. Wu, Christine Rappaport-Fuerhauser, Peter Hillemanns, Rob B. van der Luijt, Gord Glendon, Jan Lubinński, Csilla Szabo, Gillian Mitchell, Andrea L. Richardson, Mark E. Robson, Roger L. Milne, Thomas Hansen, Francesca Damiola, Tameka Shelford, Natalia Antonenkova, Julie Lecarpentier, Paul A. James, Claudine Isaacs, Gianluca Severi, Maria A. Caligo, Teodora Goranova, Kate Lawrenson, Sandra Orsulic, Priyanka Sharma, Holly R. Harris, Peter A. Fasching, Christian Sutter, Torben A Kruse, Line Bjørge, Lesley McGuffog, Leon F.A.G. Massuger, Lynne R. Wilkens, Reidun K. Kopperud, Jillian Hung, Iain A. McNeish, Hanne Meijers-Heijboer, Uffe Birk Jensen, Diether Lambrechts, Johanna Rantala, Kelly-Anne Phillips, Michelle M.M. Woo, Kathryn L. Terry, Kathleen Claes, Ellen L. Goode, Olufunmilayo I. Olopade, Darcy L. Thull, Ailith Pirie, Sharon E. Johnatty, Soo Hwang Teo, Aimee A D'Aloisio, Evgeny N. Imyanitov, Domenico Palli, Andrew Berchuck, Banu Arun, Florentia Fostira, Jan Hauke, Jenny Chang-Claude, Pamela J. Thompson, Peter J. Hulick, Per Broberg, Arjen R. Mensenkamp, Xifeng Wu, Alicia A. Tone, Jacques Simard, Ursula Eilber, Jacek Gronwald, Kenneth Blankstein, James M. Flanagan, Alvaro N.A. Monteiro, Timea Pocza, Rita K. Schmutzler, Jeffrey N. Weitzel, Simon A. Gayther, William D. Foulkes, Valerie McGuire, Katherine L. Nathanson, Kevin H. Eng, Anna deFazio, Ian G. Campbell, Capucine Delnatte, Shan Wang-Gohrke, Jenna Lilyquist, Matti A. Rookus, Sakaeva Dina Damirovna, Laure Dossus, Simon G. Coetzee, Catherine J. Kennedy, Roberta B. Ness, James Paul, Andrew Lee, Linda E. Kelemen, Judith Balmaña, Anne-Marie Gerdes, Laure Barjhoux, Håkan Olsson, Lisa Walker, Doris Steinemann, Cecilia M. Dorfling, Julie M. Cunningham, Shelley S. Tworoger, Allan Jensen, Thomas A. Sellers, Javier Benitez, Anthony N. Karnezis, Hoda Anton-Culver, Carole Brewer, Siranoush Manoukian, Dorothea Wand, Ed Dicks, Antonis C. Antoniou, Amanda E. Toland, Anna Marie Mulligan, Päivi Kannisto, Rikki Cannioto, Bernd Dworniczak, Susan J. Ramus, Anna V. Tinker, Epidemiology and Data Science, Amsterdam Reproduction & Development (AR&D), CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Government of Canada, Cancer Research Foundation, Canadian Institutes of Health Research, National Institutes of Health (US), Fonds de Recherche du Québec, Ministry of Health and Welfare (South Korea), Associazione Italiana per la Ricerca sul Cancro, Deutsche Krebshilfe, Genome Canada, Medical Oncology, Clinical Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Centre Léon Bérard [Lyon], Service de Génétique Oncologique, Institut Curie [Paris], CRLCC René Gauducheau, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre Hospitalier Métropole Savoie [Chambéry], CHU Grenoble, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Etienne, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Université Paris-Saclay, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Tyrer, Jonathan [0000-0003-3724-4757], Dennis, Joe [0000-0003-4591-1214], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Leslie, Goska [0000-0001-5756-6222], Brenton, James [0000-0002-5738-6683], Song, Honglin [0000-0001-5076-7371], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, endocrine system diseases, Epidemiology, Càncer d'ovari, Genome-wide association study, Carcinoma, Ovarian Epithelial, Genome-wide association studies, susceptibility, Risk Factors, Genotype, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Medicine and Health Sciences, Neoplasms, Glandular and Epithelial, POPULATION, Genetics & Heredity, Genetics, Ovarian Neoplasms, RISK, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], cancer, ovary, BRCA1 Protein, COMMON VARIANTS, 11 Medical And Health Sciences, ASSOCIATION, female genital diseases and pregnancy complications, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Serous fluid, ovarian cancer, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Life Sciences & Biomedicine, epithelial ovarian cancer, BRCA1, BRCA2, Population, Telomere-Binding Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, CLEAR-CELL CARCINOMA, Ovarian cancer, medicine, Journal Article, Humans, BREAST-CANCER, Genetic Predisposition to Disease, Allele, education, Genotyping, Alleles, METAANALYSIS, BRCA2 Protein, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, MUTATIONS, ENDOMETRIOSIS, Biology and Life Sciences, 06 Biological Sciences, medicine.disease, 030104 developmental biology, Genetic Loci, Mutation, TELOMERE LENGTH, Cancer research, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Developmental Biology, Genome-Wide Association Study
Abstract: The OCAC OncoArray genotyping project: et al., To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC., The OCAC OncoArray genotyping project was funded through grants from the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.) and R01-CA058598 (M.T.G.)); Canadian Institutes of Health Research (MOP-86727 (L.E.K.)); and the Ovarian Cancer Research Fund (A.B.). Funding for the CIMBA OncoArray genotyping was provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.)), the Odense University Hospital Research Foundation (M.T.), the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1420190 (S.K.P.)), the Italian Association for Cancer Research (IG16933 (L.O.)) and German Cancer Aid (110837 (R.K.S.).
Published: 2017

26. Assessment of an APOBEC3B truncating mutation, c.783delG, in patients with breast cancer

Author: Julia Enßen, Thilo Dörk, Tessa Spethmann, Natalia Antonenkova, Hans Christiansen, Robert Geffers, Tjoung-Won Park-Simon, Elza Khusnutdinova, Ariane Sadr-Nabavi, Natalia Bogdanova, Peter Hillemanns, Hoda Radmanesh, Sabin Bhuju, Fatemeh Homaei Shandiz, Peter Schürmann, and Helmholtz Centre for infection research, Inhoffenstr.7, 38124 Braunschweig, Germany.
Subjects: Adult, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Genotype, Breast Neoplasms, Biology, Bioinformatics, Frameshift mutation, Minor Histocompatibility Antigens, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Cytidine Deaminase, Internal medicine, Exome Sequencing, Odds Ratio, medicine, Humans, Genetic Predisposition to Disease, Age of Onset, Genotyping, Alleles, Genetic Association Studies, Exome sequencing, Aged, Sequence Deletion, Case-control study, Odds ratio, Middle Aged, medicine.disease, Founder Effect, 030104 developmental biology, Case-Control Studies, 030220 oncology & carcinogenesis, Female, Breast carcinoma
Abstract: APOBEC3B belongs to the family of DNA-editing enzymes. A copy number variant targeting the genomic APOBEC3A-APOBEC3B locus has a significant impact on breast cancer risk, but the relative contribution of APOBEC3B is uncertain. In this study, we investigate a loss-of-function mutation that selectively targets APOBEC3B, for its association with breast cancer risk. We performed exome sequencing on genomic DNA samples of 6 Byelorussian patients with familial breast cancer. We then studied through mutation-specific genotyping four hospital-based breast cancer case–control series from Belarus, Russia, Germany, and Iran, respectively, comprising a total of 3070 breast cancer patients and 2878 healthy females. Results were evaluated using fixed-effects meta-analyses. Exome sequencing uncovered a frameshift mutation, APOBEC3B*c.783delG, that was recurrent in the study populations. Subsequent genotyping identified this mutation in 23 additional breast cancer cases and 9 healthy female controls, with an adjusted Odds Ratio 2.29 (95% CI 1.04; 5.03, P = 0.04) in the combined analysis. There was an enrichment of the c.783delG mutation in patients with breast cancer diagnosed below 50 years of age (OR 3.22, 95% CI 1.37; 7.56, P = 0.007). APOBEC3B*c.783delG showed evidence of modest association with breast cancer and seemed to contribute to earlier onset of the disease. These results may need to be reconciled with proposals to consider APOBEC3B as a possible therapeutic target in breast cancer.
Published: 2017

27. Association analysis identifies 65 new breast cancer risk loci

Author: Michael Jones, Dong-Young Noh, Martha J. Shrubsole, Chen-Yang Shen, Xiaoqing Chen, Esther M. John, Patricia Harrington, Quinten Waisfisz, Sue K. Park, Miriam Dwek, Christa Stegmaier, Sibylle Loibl, Wing-Yee Lo, Suleeporn Sangrajrang, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Christof Sohn, Keun-Young Yoo, Arja Jukkola-Vuorinen, Kathrin Thöne, James McKay, John J. Spinelli, Brian D. Carter, Elza Khusnutdinova, Francois Bacot, Paul L. Auer, Anna H. Wu, Christopher I. Amos, Johanna I. Kiiski, Hans Wildiers, Manjeet K. Bolla, Soo Hwang Teo, Julie M. Cunningham, Zhaoming Wang, Dieter Flesch-Janys, Argyrios Ziogas, Ann Smeets, Min Hyuk Lee, Xiaohong R. Yang, Carl Blomqvist, Natalia Antonenkova, Vassilios Georgoulias, Siranoush Manoukian, Anne Lise Børresen-Dale, Montserrat Garcia-Closas, Priyanka Sharma, Michael J. Kerin, Loic Le Marchand, Yoshio Kasuga, Michael Untch, Thomas Brüning, Natalia Bogdanova, Juliet D. French, Mark E. Sherman, Diana Eccles, Don M. Conroy, Marcia Adams, Pascal Guénel, Jonine D. Figueroa, Somchai Thanasitthichai, Jonathan Beesley, Paolo Peterlongo, Angela Cox, Graham G. Giles, Hans Christiansen, Irene L. Andrulis, Caroline Baynes, V. Shane Pankratz, Kristine Jones, Wei Zheng, Motoki Iwasaki, Rita K. Schmutzler, Julian Peto, Sara Margolin, Hedy S. Rennert, Hidemi Ito, Caroline Seynaeve, Jirong Long, Rachel Lloyd, Mark S. Goldberg, Javier Benitez, Børge G. Nordestgaard, Kathleen E. Malone, A. Heather Eliassen, Valerie Rhenius, Kristan J. Aronson, Maartje J. Hooning, Ursula Eilber, Christopher A. Haiman, Ji Yeob Choi, Jaana M. Hartikainen, Ian W. Brock, Barbara Burwinkel, Brigitte Rack, Mitul Shah, Matthias W. Beckmann, Belynda Hicks, Bernardo Bonanni, Alexander Hein, Leslie Bernstein, Christine L. Clarke, Emilie Cordina-Duverger, Sabine Behrens, Hoda Anton-Culver, Angela Brooks-Wilson, Bin Zhu, Gord Glendon, Banu Arun, José A. García-Sáenz, Jose Ignacio Arias Perez, Anne Grundy, Ans M.W. van den Ouweland, Nadege Presneau, Volker Arndt, Mikael Eriksson, Simon S. Cross, Craig Luccarini, Anthony J. Swerdlow, Veli-Matti Kosma, Hui Miao, Ming-Feng Hou, Hiroji Iwata, Christi J. van Asperen, Henrik Flyger, Jennifer Stone, Qin Wang, Penny Soucy, Heli Nevanlinna, Jane Heyworth, Shoichiro Tsugane, Annika Lindblom, Curtis Olswold, Trinidad Caldés, Laura Fachal, Ed Dicks, Shirley Hui, Katja Butterbach, Alison M. Dunning, Peter Devilee, Qiuyin Cai, Antonis C. Antoniou, Diether Lambrechts, Katarzyna Kaczmarek, Katri Pylkäs, Fredrick R. Schumacher, Arif B. Ekici, Aaron D. Norman, Jolanta Lissowska, Daniel C. Tessier, N Hamel, Paolo Radice, Håkan Olsson, Vessela N. Kristensen, Ling Tong, Harald Surowy, Rulla M. Tamimi, Jonathan Tyrer, Michael P. Lux, Stacey L. Edwards, Kathryn J. Ruddy, Giske Ursin, Myrto Barrdahl, Xiao-Ou Shu, Primitiva Menéndez, Sara Y. Brucker, Elad Ziv, Kenneth Muir, Eric Hahnen, Andy C. H. Lee, Rodney J. Scott, Lothar Haeberle, Darya Prokofyeva, Isabel dos-Santos-Silva, Peter Kraft, David G. Cox, Jong Won Lee, Sunil R. Lakhani, Kelly-Anne Phillips, Douglas F. Easton, Melissa C. Southey, Jan Lubinski, Jose E. Castelao, Hanne Meijers-Heijboer, Ivana Maleva Kostovska, Siddhartha Kar, Renske Keeman, Celine M. Vachon, Diana Torres, Stephen J. Chanock, Jack A. Taylor, Emiel J. Th. Rutgers, Chuen Neng Lee, Jason Vollenweider, Gadi Rennert, Jane Romm, Amy E. McCart Reed, Kee Seng Chia, Thomas Rüdiger, Anja Rudolph, Catriona McLean, David Van Den Berg, Christopher G. Scott, Mervi Grip, Lucy Xia, Georgia Chenevix-Trench, Robert Winqvist, Mary Beth Terry, Jenny Chang-Claude, Hans-Ulrich Ulmer, Mikael Hartman, Dona N. Ho, Maria Kabisch, Christoph Engel, Claire Mulot, Grethe I. Grenaker Alnæs, Arto Mannermaa, Nazneen Rahman, Tjoung-Won Park-Simon, Atocha Romero, Lin Fritschi, Manuela Gago-Dominguez, Matthias Ruebner, Valerie Gaborieau, Keitaro Matsuo, Asha Rostamianfar, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, J.-P. Meyer, Sara Lindström, Annegien Broeks, Audrey Lemaçon, Tsun Leung Chan, Tongguang Cheng, Robert J. MacInnis, Habibul Ahsan, Federico Canzian, Paul Brennan, Mia M. Gaudet, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Jacek Gronwald, Sung-Won Kim, Daehee Kang, Daniel O. Stram, Nichola Johnson, Rob B. van der Luijt, Sten Cornelissen, Camilla Wendt, Dylan M. Glubb, Olufunmilayo I. Olopade, Usha Menon, David J. Hunter, Kristiina Aittomäki, Jamie Allen, Chiu-Chen Tseng, Keith Humphreys, Edmond S. K. Ma, Peter Hillemanns, Hiltrud Brauch, Chia-Ni Hsiung, Sheila Seal, Junko Ishiguro, Dale P. Sandler, Peter Schürmann, Gary D. Bader, Sarah Stewart-Brown, Flavio Lejbkowicz, Marike Gabrielson, Wolfgang Janni, Judith S. Brand, Jingmei Li, Ava Kwong, Stig E. Bojesen, Ying Zheng, Mila Pinchev, Yu Tang Gao, Susan E. Hankinson, Elinor J. Sawyer, Per Broberg, Sofia Khan, Grace Sheng, Alfons Meindl, Margriet Collée, Jyh-Cherng Yu, Ute Krüger, Louise A. Brinton, Elizabeth W. Pugh, Thilo Dörk, Hilary K. Finucane, Peter A. Fasching, Shan Wang-Gohrke, Jenna Lilyquist, Muriel A. Adank, Marjanka K. Schmidt, Susan M. Gapstur, Sune F. Nielsen, Maya Ghoussaini, Minouk J. Schoemaker, Roger L. Milne, Jacques Simard, Clarice R. Weinberg, Kyriaki Michailidou, Shivaani Mariapun, Rob A. E. M. Tollenaar, Lizet E. van der Kolk, Nicola Miller, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Ross L. Prentice, Anna Marie Mulligan, Jason S. Carroll, Taiki Yamaji, Carolina Ellberg, Mingajeva Elvira, Olivia Fletcher, Arnaud Droit, Per Hall, Maria Elena Martinez, Maria Tengström, Hui Cai, Xia Jiang, Janet E. Olson, Julia A. Knight, Nick Orr, Angel Carracedo, Guanmengqian Huang, Martine Dumont, Cheng Har Yip, Tom Maishman, Mary B. Daly, Artitaya Lophatananon, Niclas Håkansson, Steven N. Hart, Nur Aishah Taib, Andreas Schneeweiss, Daniel F. Schmidt, Daniel Vincent, Antoinette Hollestelle, Dimitrios Mavroudis, JoAnn E. Manson, Joe Dennis, Walter C. Willett, Rudolf Kaaks, Karen McCue, Enes Makalic, Kimberly F. Doheny, Eunjung Lee, Robert N. Hoover, Fergus J. Couch, Ute Hamann, Alice S. Whittemore, Hermann Brenner, Lorraine Durcan, Kamila Czene, Patrick Neven, John L. Hopper, Clinical Genetics, Medical Oncology, Human Genetics, CCA - Cancer biology and immunology, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Tyrer, Jonathan [0000-0003-3724-4757], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Allen, Jamie [0000-0002-8677-2225], Fachal Vilar, Laura [0000-0002-7256-9752], Carroll, Jason [0000-0003-3643-0080], Rhenius, Valerie [0000-0003-4215-3235], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
Subjects: 0301 basic medicine, Multifactorial Inheritance, Genome-wide association study, Regulatory Sequences, Nucleic Acid, skin and connective tissue diseases, Cancer genetics, Genetics, Multidisciplinary, medicine.diagnostic_test, 3. Good health, Europe, annotation, Medical genetics, Female, Asian Continental Ancestry Group, medicine.medical_specialty, Asia, architecture, European Continental Ancestry Group, ABCTB Investigators, Locus (genetics), Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, White People, NBCS Collaborators, 03 medical and health sciences, Breast cancer, Asian People, SDG 3 - Good Health and Well-being, Genetic variation, ConFab/AOCS Investigators, expression, medicine, Genetic predisposition, Journal Article, Humans, Computer Simulation, Genetic Predisposition to Disease, biological pathways, Genetic association, Genetic testing, Genetic association study, Binding Sites, interaction networks, medicine.disease, comprehensive molecular portraits, mutations, susceptibility loci, 030104 developmental biology, Genetic Loci, genome-wide association, protein, Transcription Factors, Genome-Wide Association Study
Abstract: Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P
Published: 2017

28. Prevalence of the BLM nonsense mutation, p.Q548X, in ovarian cancer patients from Central and Eastern Europe

Author: Janusz Limon, Zalina Takhirova, Alina Kuźniacka, Cezary Cybulski, Ingo B. Runnebaum, Jacek Gronwald, Wojtek Kluźniak, Magdalena Ratajska, Tatiana V. Gorodnova, Tjoung-Won Park-Simon, Evgeny N. Imyanitov, Anna P. Sokolenko, Thilo Dörk, Amira Podolak, Grigoriy A. Yanus, Darya Prokofyeva, Alexandr V. Togo, Elza Khusnutdinova, Vilius Rudaitis, Theresa Tarp, Natalia Antonenkova, Matthias Dürst, Peter Hillemanns, Dominika Wokołorczyk, Maciej Stukan, Natalia Bogdanova, Danuta Vasilevska, Jan Lubinski, and Marina Bermisheva
Subjects: Adult, Oncology, Cancer Research, medicine.medical_specialty, Pathology, Nonsense mutation, Biology, Polymerase Chain Reaction, Breast cancer, Ovarian carcinoma, Internal medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Risk factor, Family history, Alleles, Genetics (clinical), Aged, Ovarian Neoplasms, RecQ Helicases, Cancer, Middle Aged, medicine.disease, Founder Effect, Europe, Codon, Nonsense, Mutation (genetic algorithm), Female, Ovarian cancer
Abstract: A nonsense mutation, p.Q548X, in the BLM gene has recently been associated with an increased risk for breast cancer. In the present work, we investigated the prevalence of this Slavic founder mutation in 2,561 ovarian cancer cases from Russia, Belarus, Poland, Lithuania or Germany and compared its frequency with 6,205 ethnically matched healthy female controls. The p.Q548X allele was present in nine ovarian cancer patients of Slavic ancestry (0.5 %; including one case with concurrent BRCA1 mutation). The mutation was not significantly more frequent in cases than in controls (Mantel-Haenszel OR 1.14, 95 % CI 0.49; 2.67). Ovarian tumours in p.Q548X carriers were mainly of the serous subtype, and there was little evidence for an early age at diagnosis or pronounced family history of cancer. These findings indicate that the BLM p.Q548X mutation is not a strong risk factor for ovarian cancer.
Published: 2014

29. Prevalence of PALB2 mutation c.509_510delGA in unselected breast cancer patients from Central and Eastern Europe

Author: Elza Khusnutdinova, Hans Christiansen, Natalia Bogdanova, Natalia Antonenkova, Thilo Dörk, Peter Hillemanns, Monika Noskowicz, Marina Bermisheva, Michael Bremer, Zalina Takhirova, and Tjoung-Won Park-Simon
Subjects: Adult, Oncology, Cancer Research, medicine.medical_specialty, Republic of Belarus, PALB2, DNA Mutational Analysis, Estrogen receptor, Breast Neoplasms, Penetrance, White People, Russia, Breast cancer, Germany, Internal medicine, Epidemiology, Genetics, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Family history, skin and connective tissue diseases, Alleles, Genetics (clinical), Aged, Sequence Deletion, Aged, 80 and over, Base Sequence, business.industry, Tumor Suppressor Proteins, Carcinoma, Ductal, Breast, Nuclear Proteins, Cancer, Middle Aged, medicine.disease, Carcinoma, Lobular, Case-Control Studies, Female, Fanconi Anemia Complementation Group N Protein, business
Abstract: Inherited mutations in PALB2 are known to be associated with increased breast cancer risk. We aimed to investigate the prevalence and risk association of a recurrent PALB2 mutation, c.509_510delGA, among 3,924 unselected breast cancer patients from Belarus, Russia or Germany. High-resolution melting analyses and direct sequencing identified the c.509_510delGA allele in 3/1,008 (0.3 %) German breast cancer patients, 2/994 (0.2 %) Russian breast cancer patients and 5/1,922 (0.3 %) Byelorussian breast cancer patients. Breast tumours were mainly estrogen receptor positive and included both ductal and lobular histology. Only one of the ten patients had a first-degree family history of breast cancer. The mutation was not detected in 2,827 healthy females from the same populations, confirming the association of PALB2*c.509_510delGA with breast cancer risk (p = 0.007). These data indicate that the PALB2*c.509_510delGA mutation is prevalent in about 1 in 400 breast cancer patients from Central and Eastern Europe, and the low occurrence of familial clustering is consistent with a moderate penetrance of this mutation.
Published: 2013

30. Nonsense mutation p.Q548X in BLM, the gene mutated in Bloom’s syndrome, is associated with breast cancer in Slavic populations

Author: Nurzhan Turmanov, Elza Khusnutdinova, Shamil Gantsev, Darya Prokofyeva, Thilo Dörk, Zalina Takhirova, Natalia Dubrowinskaja, Natalia Antonenkova, Natalia Bogdanova, Hans Christiansen, Ihor Datsyuk, Tjoung-Won Park-Simon, Peter Hillemanns, and Marina Bermisheva
Subjects: Adult, Oncology, Heterozygote, Cancer Research, medicine.medical_specialty, Republic of Belarus, Nonsense mutation, Breast Neoplasms, Biology, medicine.disease_cause, Breast cancer, Internal medicine, Chromosome instability, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Allele, Aged, Aged, 80 and over, Genetics, Mutation, RecQ Helicases, Incidence (epidemiology), Middle Aged, Bashkiria, medicine.disease, Kazakhstan, Codon, Nonsense, Case-Control Studies, Female, Ukraine, Breast carcinoma
Abstract: Bloom's syndrome is a rare autosomal recessive chromosomal instability disorder with a high incidence of various types of neoplasia, including breast cancer. Whether monoallelic BLM mutations predispose to breast cancer has been a long-standing question. A nonsense mutation, p.Q548X, has recently been associated with an increased risk for breast cancer in a Russian case-control study. In the present work, we have investigated the prevalence of this Slavic BLM founder mutation in a total of 3,188 breast cancer cases and 2,458 controls from Bashkortostan, Belarus, Ukraine, and Kazakhstan. The p.Q548X allele was most frequent in Russian patients (0.8 %) but was also prevalent in Byelorussian and Ukrainian patients (0.5 and 0.6 %, respectively), whereas it was absent in Altaic or other non-European subpopulations. In a combined analysis of our four case-control series, the p.Q548X mutation was significantly associated with breast cancer (Mantel-Haenszel OR 5.1, 95 % CI 1.2; 21.9, p = 0.03). A meta-analysis with the previous study from the St. Petersburg area corroborates the association (OR 5.7, 95 % CI 2.0; 15.9, p = 3.7 × 10(-4)). A meta-analysis for all published truncating mutations further supports the association of BLM with breast cancer, with an estimated two- to five-fold increase in risk (OR 3.3, 95 %CI 1.9; 5.6, p = 1.9 × 10(-5)). Altogether, these data indicate that BLM is not only a gene for Bloom's syndrome but also might represent a breast cancer susceptibility gene.
Published: 2012

31. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Author: Francesmary Modugno, Alice S. Whittemore, Kunle Odunsi, Heli Nevanlinna, Fiona Bruinsma, Iwona K. Rzepecka, Jolanta Lissowska, Malcolm C. Pike, Bu-Tian Ji, Michelle A.T. Hildebrandt, Warren Davis, Agnieszka Dansonka-Mieszkowska, Line Bjørge, Roberta B. Ness, James Paul, Katja K.H. Aben, Nonna Kolomeyevskaya, Melissa C. Southey, Bridget Kruszka, Daniel W. Cramer, Shashikant Lele, Edwin S. Iversen, Kristina Schmitt, Julie M. Cunningham, Xifeng Wu, Celeste Leigh Pearce, Keitaro Matsuo, Cezary Cybulski, Linda E. Kelemen, Kirsten B. Moysich, Kristine G. Wicklund, Ralf Bützow, Shelley S. Tworoger, Grace Friel, Robert P. Edwards, Agnieszka Timorek, Leah Preus, Anna Jakubowska, Paul D.P. Pharoah, Karen Lu, Lambertus A. Kiemeney, Allan Jensen, Elisa V. Bandera, Steven A. Narod, Soo-Hwang Teo, Susanne K. Kjaer, Jonathan Tyrer, Joseph H. Rothstein, Irene Orlow, Rachel Palmieri Weber, Janine M. Joseph, Anna M. van Altena, Mary Nesline, Rüdiger Klapdor, Hannah P. Yang, Graham G. Giles, Pamela J. Thompson, Christine Walsh, Jolanta Kupryjanczyk, Wei Zheng, Nicolas Wentzensen, Angela Brooks-Wilson, Arto Leminen, Philipp Harter, Nadeem Siddiqui, Joanna Moes-Sosnowska, Yin Ling Woo, Anja Rudolph, John R. McLaughlin, Louise A. Brinton, Ingo B. Runnebaum, Shalaka S. Hampras, Linda S. Cook, Lotte Nedergaard, Lara E. Sucheston-Campbell, Natalia Bogdanova, Alexander Hein, Joseph L. Kelley, Claus Høgdall, Matthias Dürst, Jennifer A. Doherty, Ignace Vergote, Argyrios Ziogas, Ian G. Campbell, Prashant Singh, Hoda Anton-Culver, Shan Wang-Gohrke, Helga B. Salvesen, Stefan Nickels, Ingvild L. Tangen, Joe Dennis, Georgia Chenevix-Trench, Eva S. Schernhammer, Paul K. Wallace, Leon F.A.G. Massuger, Lynne R. Wilkens, Ed Dicks, Yukie Bean, Alice W. Lee, Ian McNeish, Evelyn Despierre, Patricia Harrington, Kevin H. Eng, Maria Bisogna, Nhu D. Le, Sandrina Lambrechts, Andrew Berchuck, Honglin Song, Hanis Nazihah Hasmad, Nils Schoof, Diana Eccles, Harvey A. Risch, Xiao-Ou Shu, Rosalind Glasspool, Peter Hillemanns, Jenny Permuth-Wey, Chi-Chen Hong, Catherine M. Phelan, Marc T. Goodman, Peter A. Fasching, Matthias W. Beckmann, Helen Baker, Doug Easton, Robert A. Vierkant, Barbara Perkins, Lene Lundvall, Elizabeth M. Poole, Joanna Plisiecka-Halasa, Arif B. Ekici, Melissa Kellar, Jan Lubinski, Alyssa Clay, Diether Lambrechts, Jacek Gronwald, Keith L. Knutson, Karen Carty, Camilla Krakstad, Jenny Lester, Simon A. Gayther, Ya-Yu Tsai, Rikki Cannioto, Kathryn L. Terry, Ira Schwaab, Susan J. Ramus, Andreas du Bois, Thomas A. Sellers, Estrid Høgdall, Valeria McGuire, Yurii B. Shvetsov, Joellen M. Schildkraut, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Sara H. Olson, Ellen L. Goode, Song Liu, Usha Menon, Dong Liang, Tanja Pejovic, Yu-Tang Gao, Florian Heitz, Beth Y. Karlan, Brooke L. Fridley, Mary Anne Rossing, Thilo Dörk, Douglas A. Levine, Weiva Sieh, Liisa M. Pelttari, Anna H. Wu, Natalia Antonenkova, Satoyo Hosono, Dennis, Joe [0000-0003-4591-1214], Dicks, Ed [0000-0002-0617-0401], Easton, Douglas [0000-0003-2444-3247], Song, Honglin [0000-0001-5076-7371], Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, endocrine system diseases, Carcinoma, Ovarian Epithelial, T-Lymphocytes, Regulatory, 0302 clinical medicine, STAGE, Gene Frequency, Risk Factors, Genotype, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], immunosuppression, Middle Aged, Protein-Serine-Threonine Kinases, female genital diseases and pregnancy complications, 3. Good health, TGFBR2, Gene Expression Regulation, Neoplastic, Serous fluid, ovarian cancer, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Adenocarcinoma, Female, Life Sciences & Biomedicine, EXPRESSION, Adult, CARCINOMA, Population, chemical and pharmacologic phenomena, Single-nucleotide polymorphism, FCGR2B, Protein Serine-Threonine Kinases, PERIPHERAL-BLOOD, Biology, DENDRITIC CELLS, Polymorphism, Single Nucleotide, 03 medical and health sciences, LUNG-CANCER, medicine, BREAST-CANCER, Humans, Genetic Predisposition to Disease, REGULATORY T-CELLS, education, Aged, Science & Technology, RECEPTOR, Receptor, Transforming Growth Factor-beta Type II, biomarkers, Cell Biology, medicine.disease, 030104 developmental biology, FC-GAMMA-RIIB, Immunology, genetic variation, Cancer research, Ovarian cancer, Receptors, Transforming Growth Factor beta, Clear cell, Priority Research Paper, Adenocarcinoma, Clear Cell
Abstract: Contains fulltext : 167177.pdf (Publisher’s version ) (Open Access) BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.
Published: 2016

32. Age- and Tumor Subtype Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers

Author: Sten Cornelissen, Richard van Hien, Muriel A. Adank, Argyrios Ziogas, Amy Trentham-Dietz, Frans B. L. Hogervorst, Hiltrud Brauch, Alison M. Dunning, Qin Wang, Stig E. Bojesen, Natalia Bogdanova, Hoda Anton-Culver, Sara Margolin, Elza Khusnutdinova, Marjanka K. Schmidt, Elinor J. Sawyer, Kenneth Offit, Lothar Haeberle, Veli-Matti Kosma, Natalia Antonenkova, Taru A. Muranen, Heli Nevanlinna, Polly A. Newcomb, Manjeet K. Bolla, Mieke Schutte, Vessela N. Kristensen, Andy C. H. Lee, Melissa C. Southey, Jenny Chang-Claude, Douglas F. Easton, Marina Bermisheva, Henrik Flyger, Lizet E. van der Kolk, Antonis C. Antoniou, Anna Jakubowska, Paul D.P. Pharoah, Ans M.W. van den Ouweland, Jan Lubinski, Angela Cox, Maartje J. Hooning, Graham G. Giles, Rita K. Schmutzler, Julian Peto, Anthony J. Swerdlow, Volker Arndt, Thilo Dörk, Barbara Burwinkel, Harald Surowy, Ian Tomlinson, Celine M. Vachon, Peter Hillemanns, Mark E. Robson, Michael Jones, Roger L. Milne, Esther M. John, Olivia Fletcher, Julie Soens, Per Hall, Quinten Waisfisz, Jonine D. Figueroa, Julia A. Knight, Rob A. E. M. Tollenaar, Irene L. Andrulis, Annika Lindblom, Annegien Broeks, Alfons Meindl, Peter A. Fasching, Montserrat Garcia-Closas, Georgia Chenevix-Trench, Thomas Brüning, Alice S. Whittemore, Caroline M. Seynaeve, Tjoung-Won Park-Simon, Eva Galle, Hermann Brenner, Hanne Meijers, Amanda B. Spurdle, Antoinette Hollestelle, Kamila Czene, Anja Rudolph, John L. Hopper, Arto Mannermaa, Simon S. Cross, Fergus J. Couch, Human genetics, CCA - Cancer biology, Antoniou, Antonis [0000-0001-9223-3116], Dunning, Alison [0000-0001-6651-7166], Lee, Andrew [0000-0003-0677-0252], Pharoah, Paul [0000-0001-8494-732X], Wang, Jean [0000-0002-9139-0627], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Clinical Genetics, and Medical Oncology
Subjects: 0301 basic medicine, Oncology, Cancer Research, Estrogen receptor, Disease, 0302 clinical medicine, Receptors, 80 and over, Odds Ratio, 2.1 Biological and endogenous factors, Aetiology, skin and connective tissue diseases, Progesterone, Cancer, Sequence Deletion, Aged, 80 and over, education.field_of_study, Homozygote, Age Factors, ORIGINAL REPORTS, Middle Aged, 3. Good health, Receptors, Estrogen, 030220 oncology & carcinogenesis, Female, Risk assessment, Receptors, Progesterone, Adult, medicine.medical_specialty, Heterozygote, Clinical Sciences, Oncology and Carcinogenesis, Population, Breast Neoplasms, Risk Assessment, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Clinical Research, Internal medicine, Breast Cancer, Genetics, medicine, Humans, Genetic Predisposition to Disease, Oncology & Carcinogenesis, education, CHEK2, Aged, business.industry, Case-control study, Odds ratio, medicine.disease, Estrogen, Checkpoint Kinase 2, 030104 developmental biology, Case-Control Studies, business
Abstract: Purpose CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC. Patients and Methods CHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies. Results Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center–based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10−20). The OR was higher for estrogen receptor (ER)–positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10−21]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10−4). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom. Conclusion These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up.
Published: 2016

33. 9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: evidence from the Breast Cancer Association Consortium

Author: Javier Benitez, Frederik Marmé, Nichola Johnson, Ian W. Brock, Fiona M. Blows, Natalia Bogdanova, Arto Mannermaa, Peter Hillemanns, Hoda Anton-Culver, Anthony J. Swerdlow, Roger L. Milne, Jonathan Beesley, Veli-Matti Kosma, Guzel Zinnatullina, Paolo Peterlongo, Irene L. Andrulis, Annika Lindblom, Dieter Flesch-Janys, Ann Smeets, Arif B. Ekici, Pascal Guénel, Vesa Kataja, Thomas Brüning, Graham G. Giles, Isabel dos-Santos-Silva, Douglas F. Easton, Yuriy Rogov, Ruediger Schulz-Wendtland, Pierre Laurent-Puig, Thilo Dörk, Malcolm W.R. Reed, Heiko Müller, Linda M. Braaf, Janet E. Olson, Cariona A. McLean, Leslie Bernstein, Elinor J. Sawyer, Jaana M. Hartikainen, Siranoush Manoukian, Robert Paridaens, Marina Bermisheva, Natalia Antonenkova, Ian Tomlinson, Thérèse Truong, Minouk J. Schoemaker, Anna Marie Mulligan, Elza Khusnutdinova, Xianshu Wang, Christof Sohn, Katri Pylkäs, Caroline M. Seynaeve, Christina Clarke Dur, Caroline Weltens, Sune F. Nielsen, Carl Blomqvist, Nick Orr, Hiltrud Brauch, Maryam Mahmoodi, Shan Wang-Gohrke, Melissa C. Southey, Fergus J. Couch, Olivia Fletcher, Mervi Grip, Nayana Weerasooriya, Georgia Chenevix-Trench, Rita K. Schmutzler, Julian Peto, Jenny Chang-Claude, Peter Schürmann, Frank Dudbridge, John W.M. Martens, Robert Winqvist, Surapon Wiangnon, Celine M. Vachon, Arkom Chaiwerawattana, Hermann Brenner, Artitaya Lophatananon, Arja Jukkola-Vuorinen, Peter A. Fasching, Børge G. Nordestgaard, Manjeet K. Humphreys, Barbara Burwinkel, Kristiina Aittomäki, Marjanka K. Schmidt, Argyrios Ziogas, Michael Bremer, Paul D.P. Pharoah, Loris Bernard, Alexander Miron, Sara Margolin, Kamila Czene, Diether Lambrechts, Claus R. Bartram, Annegien Broeks, Maya Ghoussaini, John L. Hopper, Simon S. Cross, Matthias W. Beckmann, Per Hall, Agnes Jager, Stig E. Bojesen, Michael Jones, Darya Prokofyeva, Julia A. Knight, Alan Ashworth, Taru A. Muranen, Xiaoqing Chen, Esther M. John, Claire Mulot, Alfons Meindl, Ursula Eilber, Laura Baglietto, José Ignacio Arias-Perez, Peter Devilee, Henrik Flyger, Sten Cornelissen, Jingmei Li, Katharina Buck, Carmel Apicella, Michael J. Kerin, Gianluca Severi, Alison M. Dunning, Kenneth Muir, Anne Langheinz, Andreas Schneeweiss, Heli Nevanlinna, Michael Golatta, Christina Justenhoven, Antoinette Hollestelle, Jianjun Liu, Helen R. Warren, Sabine Behrens, Madeleine M.A. Tilanus-Linthorst, Angela Cox, Maartje J. Hooning, Qin Wang, Paolo Radice, Volker Arndt, Robert A.E.M. Tollenaar, M. Pilar Zamora, Medical Oncology, Surgery, and Clinical Genetics
Subjects: Oncology, Pathology, Epidemiology, Estrogen receptor, population, Genome-wide association study, genetic risk, 0302 clinical medicine, Receptors, common variants, Progesterone, 0303 health sciences, education.field_of_study, identifies 2, Chromosome Mapping, Single Nucleotide, Middle Aged, 5p12, 3. Good health, Receptors, Estrogen, 030220 oncology & carcinogenesis, alleles, Female, Chromosomes, Human, Pair 9, Receptors, Progesterone, linkage, Human, Pair 9, medicine.medical_specialty, Population, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Chromosomes, Article, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Polymorphism, Allele, education, Aged, 030304 developmental biology, menarche, Case-control study, Cancer, medicine.disease, confer susceptibility, Estrogen, Case-Control Studies, genome-wide association, Genome-Wide Association Study
Abstract: Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). Methods: To further investigate the rs865686–breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case–control studies (48,394 cases, 50,836 controls). Results: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10−29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10−143], but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor–positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86–0.91; P = 3.13 × 10−22) but less strongly, if at all, with ER-negative (ER−) disease (OR, 0.98; 95% CI, 0.94–1.02; P = 0.26; Phet = 1.16 × 10−6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors. Conclusions: This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer. Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype. Cancer Epidemiol Biomarkers Prev; 21(10); 1783–. ©2012 AACR.
Published: 2016

34. 11q13 is a susceptibility locus for hormone receptor positive breast cancer

Author: Dong Young Noh, Pascal Guénel, Graeme Elliott, Vesa Kataja, Shamil Gancev, Xianshu Wang, Shan Wang-Gohrke, Annegien Broeks, Florence Menegaux, Hans Wildiers, Richard van Hien, Natalia Bogdanova, Jean Wang, Puttisak Puttawibul, Betül T. Yesilyurt, Peter Devilee, Gord Glendon, Katri Pylkäs, Mark E. Sherman, Jenny Chang-Claude, Federik Marme, Michael Bremer, Katarzyna Durda, Sarah Schott, Vessela N. Kristensen, Paolo Radice, Teresa Selander, Kamila Czene, Alfons Meindl, Gianluca Severi, Angela Cox, Maartje J. Hooning, Claus R. Bartram, John L. Hopper, Ursel Eilber, Michael Jones, M. Pilar Zamora, Stephen J. Chanock, Laura Baglietto, Caroline M. Seynaeve, Daehee Kang, Thilo Dörk, Rita K. Schmutzler, Julian Peto, Børge G. Nordestgaard, Loris Bernard, Stig E. Bojesen, Barbara Burwinkel, Douglas F. Easton, Arif B. Ekici, kConFab Investigators, Mervi Grip, Robert A.E.M. Tollenaar, Argyrios Ziogas, Jonathan Beesley, Paolo Peterlongo, Volker Arndt, Xiaoqing Chen, Nichola Johnson, Jaana M. Hartikainen, Ming-Feng Hou, Diether Lambrechts, Ruediger Schulz-Wendtland, Jan Lubinski, Taru A. Muranen, Heli Nevanlinna, Esther M. John, Graham G. Giles, Chen-Yang Shen, Jolanta Lissowska, Ian W. Brock, Grethe I. Grenaker Alnæs, Gillian S. Dite, Charlotte Lanng, Hiltrud Brauch, Anthony J. Swerdlow, MC Southey, Christina Justenhoven, Manjeet K. Humphreys, Keun-Young Yoo, Elinor J. Sawyer, Emilie Cordina-Duverger, Jose Ignacio Arias Perez, Fergus J. Couch, Peter Schürmann, Stefan Nickels, Jianjun Liu, Marjanka K. Schmidt, Zachary S. Fredericksen, Yuri I. Rogov, Ute Hamann, Elza Khusnutdinova, Hermann Brenner, Sara Margolin, Natalia Antonenkova, Peter A. Fasching, Matthias W. Beckmann, Johann H. Karstens, Montserrat Garcia-Closas, Patrick Neven, Thomas Brüning, Carl Blomqvist, Heiko Müller, Jyh Cherng Yu, Katarzyna Jaworska, Yon Ko, Pei Ei Wu, Arto Mannermaa, Rebecca Hein, Darya Prokofieva, Melissa C. Southey, Andreas Schneeweiss, Irene L. Andrulis, Christa Stegmaier, Robert Winqvist, Annika Lindblom, Anna Jakubowska, Paul D.P. Pharoah, Peter Hillemanns, Alexander Miron, Roger L. Milne, Marina Bermisheva, Dieter Flesch-Janys, Christof Sohn, Nicola Miller, Georgia Chenevix-Trench, Kristiina Aittomäki, Ian Tomlinson, Thérèse Truong, Anna Marie Mulligan, Siranoush Manoukian, Robert Paridaens, Anne Lise Børresen-Dale, Suthee Rattanamongkongul, Olivia Fletcher, Simon S. Cross, Artitaya Lophatananon, Isabel dos Santos Silva, Janet E. Olson, Nick Orr, Per Hall, Alan Ashworth, Javier Benitez, Hoda Anton-Culver, Veli-Matti Kosma, Alison M. Dunning, Kenneth Muir, Sten Cornelissen, Carmel Apicella, Arja Jukkola-Vuorinen, Michael J. Kerin, ~, and Medical Oncology
Subjects: Oncology, hormone receptor status, Estrogen receptor, Genome-wide association study, 0302 clinical medicine, Risk Factors, Genotype, Receptors, single-nucleotide polymorphisms, common variants, Pair 11, Progesterone, Genetics (clinical), Genetics, 0303 health sciences, repair genes, Single Nucleotide, identifies 5, 11q13, Breast cancer susceptibility, Genome-wide association, Hormone receptor status, Polymorphisms, Risk factors, Breast Neoplasms, Chromosomes, Human, Pair 11, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Receptors, Estrogen, Receptors, Progesterone, 3. Good health, ovarian-cancer, 030220 oncology & carcinogenesis, Human, brca1 mutations, medicine.medical_specialty, Single-nucleotide polymorphism, Biology, Chromosomes, Article, White People, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Progesterone receptor, medicine, Polymorphism, 030304 developmental biology, breast cancer susceptibility, Odds ratio, tumor characteristics, medicine.disease, confer susceptibility, Estrogen, genome-wide association, family registry, Ovarian cancer, polymorphisms
Abstract: Journal article A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P â ¤ 3 Ã 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 Ã 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype. EC Seventh Framework Programme - grant number HEALTH-F2-2009-223175 peer-reviewed
Published: 2016

35. Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

Author: Joseph L. Kelley, Michelle A.T. Hildebrandt, Diana Eccles, Karen Lu, Elisa V. Bandera, Steven A. Narod, Linda S. Cook, Matthias W. Beckmann, John R. McLaughlin, Liisa M. Pelttari, Elizabeth M. Poole, Arto Leminen, Jennifer A. Doherty, Argyrios Ziogas, Weiva Sieh, Maria Bisogna, Stuart MacGregor, Andrew Berchuck, Agnieszka Timorek, Ralf Bützow, Hoda Anton-Culver, Robert P. Edwards, Peter Hillemanns, Anja Rudolph, Joseph H. Rothstein, Agnieszka Dansonka-Mieszkowska, Aleksandra Gentry-Maharaj, Ignace Vergote, Louise A. Brinton, Meir J. Stampfer, Honglin Song, Jenny Chang-Claude, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Graham G. Giles, Valerie McGuire, Reidun K. Kopperud, Daniel W. Cramer, Alice S. Whittemore, Jacek Gronwald, Gabriel Cuellar-Partida, Georgia Chenevix-Trench, Ellen L. Goode, Stacey J. Winham, Julie M. Cunningham, Estrid Høgdall, Adriaan Vanderstichele, Jan Lubinski, Lukasz Szafron, Peter A. Fasching, Jonathan Tyrer, Alexander Hein, Harvey A. Risch, Ian G. Campbell, Joellen M. Schildkraut, Shelley S. Tworoger, C. Blake Gilks, Allan Jensen, Natalia Bogdanova, Helga B. Salvesen, Rikki Cannioto, Shan Wang-Gohrke, Terry K. Morgan, Susan J. Ramus, Catherine M. Phelan, Kirsten B. Moysich, Usha Menon, Penelope M. Webb, Angela Brooks-Wilson, Ingo B. Runnebaum, Anna H. Wu, Celeste Leigh Pearce, Suzanne C. Dixon, Dong Liang, Yi Lu, Natalia Antonenkova, Diether Lambrechts, Stacey A. Missmer, Brooke L. Fridley, Roberta B. Ness, Mary Anne Rossing, Thilo Dörk, Stefanie Burghaus, Douglas A. Levine, Marc T. Goodman, Susanne K. Kjaer, Britton Trabert, Kathryn L. Terry, Claus Høgdall, Tomasz Kluz, Heli Nevanlinna, Line Bjørge, Francesmary Modugno, Jolanta Lissowska, Fanny Dao, Simon A. Gayther, Katja K.H. Aben, Leon F.A.G. Massuger, Fiona Bruinsma, Xifeng Wu, Matthias Dürst, Jolanta Kupryjanczyk, Nicolas Wentzensen, Katharina Bischof, Els Van Nieuwenhuysen, Nhu D. Le, and Sara H. Olson
Subjects: 0301 basic medicine, endocrine system diseases, Genome-wide association study, Australian Ovarian Cancer Study, Carcinoma, Ovarian Epithelial, 0302 clinical medicine, Neoplasms, Ovarian Epithelial, Genotype, Pathology, 2.1 Biological and endogenous factors, Neoplasms, Glandular and Epithelial, Pathology, Molecular, Aetiology, Genetics (clinical), Cancer, Genetics, Ovarian Neoplasms, Genetics & Heredity, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Glandular and Epithelial, Single Nucleotide, female genital diseases and pregnancy complications, 3. Good health, Ovarian Cancer, Serous fluid, 030220 oncology & carcinogenesis, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Clear cell carcinoma, Female, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, Paediatrics and Reproductive Medicine, 03 medical and health sciences, Rare Diseases, Complementary and Alternative Medicine, medicine, Humans, Polymorphism, Carcinoma, Human Genome, Molecular, Heritability, medicine.disease, Genetic architecture, 030104 developmental biology, Ovarian cancer
Abstract: Contains fulltext : 171782.pdf (Publisher’s version ) (Closed access) Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 +/- 1.1 %), endometrioid ([Formula: see text] = 3.2 +/- 1.6 %), clear cell ([Formula: see text] = 6.7 +/- 3.3 %) and all EOC ([Formula: see text] = 5.6 +/- 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.
Published: 2016

36. Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Author: Kenneth Offit, Hoda Anton-Culver, Ans M.W. van den Ouweland, Siranoush Manoukian, Christine L. Clarke, Kyriaki Michailidou, Antonis C. Antoniou, Maria Kabisch, Isabel dos-Santos-Silva, Douglas F. Easton, Curtis Olswold, Graham G. Giles, Tien Yin Wong, Ursula Eilber, Mads Thomassen, Christopher A. Haiman, Alice J. Sigurdson, Lothar Haeberle, Florence Menegaux, Ana Osorio, Marco Montagna, Katarzyna Jaworska-Bieniek, Eitan Friedman, Simon S. Cross, Daniel Barrowdale, Elinor J. Sawyer, Adam N. Freeman, Caroline Seynaeve, Min Hyuk Lee, Arnaud Droit, Per Hall, Minouk J. Schoemaker, Trinidad Caldés, Peter Hillemanns, Frederik Marmé, Jenny Lester, Michele M. Doody, Bernard Peissel, Peter Kraft, Elza Khusnutdinova, Anna H. Wu, Stéphanie Peeters, Georg Pfeiler, Pascal Guénel, Hidemi Ito, Xingyi Guo, Antoinette Hollestelle, Heli Nevanlinna, Kathleen Claes, Ylva Paulsson-Karlsson, Cecilia M. Dorfling, Roger L. Milne, Daehee Kang, Judith S. Brand, Diether Lambrechts, Olufunmilayo I. Olopade, Simona Agata, Saundra S. Buys, Muhammad Usman Rashid, Fabienne Lesueur, Alicia Beeghly-Fadiel, Peter Devilee, Manjeet K. Bolla, Natalia Antonenkova, Irene Konstantopoulou, Claudine Isaacs, Anja Rudolph, Carl Blomqvist, Tjoung Won Park-Simon, Judy Garber, Csilla Szabo, Francois Bacot, Arto Mannermaa, Yu-Tang Gao, Stig E. Bojesen, Susan L. Neuhausen, Marina Bermisheva, Qiuyin Cai, Zakaria Einbeigi, Christian F. Singer, Qin Wang, Kerstin Rhiem, Sofia Khan, Fiona Lalloo, Robert L. Nussbaum, Thilo Dörk, William J. Blot, Sylvie Mazoyer, Julia A. Knight, Katherine L. Nathanson, Clare Turnbull, Nazneen Rahman, Anne Lise Børresen-Dale, Chuen Neng Lee, Annegien Broeks, Martha J. Shrubsole, Ava Kwong, Jirong Long, Ian G. Campbell, Sara Margolin, Fergus J. Couch, Laima Tihomirova, Mary Beth Terry, Jenny Chang-Claude, Alice S. Whittemore, Joseph Vijai, Alfons Meindl, Xiao-Ou Shu, Shan Wang-Gohrke, Wei Zheng, Beth Y. Karlan, Jacques Simard, Angela Cox, Shahana Ahmed, Polly A. Newcomb, Ritu Salani, Chen-Yang Shen, Adalgeir Arason, Sandrine Tchatchou, Ute Hamann, Elizabeth J. van Rensburg, Michael Jones, Mark H. Greene, Anthony J. Swerdlow, Senno Verhoef, Jonine Figueroa, Hermann Brenner, Volker Arndt, Charles Joly Beauparlant, Esther M. John, Nadege Presneau, Jingmei Li, Laura Papi, Marjanka K. Schmidt, Montserrat Garcia-Closas, Uffe Birk Jensen, Georgia Chenevix-Trench, Paolo Peterlongo, Penny Soucy, Thomas Brüning, Jaana M. Hartikainen, Siddhartha Kar, Ji Yeob Choi, Manuel R. Teixeira, Phuong L. Mai, Alex Teulé, Jyh Cherng Yu, Paul Brennan, Maya Ghoussaini, Edith Olah, Henrik Flyger, Michael Friedlander, Soo Hwang Teo, Frans B. L. Hogervorst, Kathleen M. Egan, David J. Hunter, Kristiina Aittomäki, Joe Dennis, Anna González-Neira, Mikael Hartman, Alison M. Dunning, Doris Steinemann, Debra Frost, Melissa C. Southey, Ramunas Janavicius, Evgeny N. Imyanitov, Catherine M. Phelan, Amanda E. Toland, Anna Marie Mulligan, David ven den Berg, Rita K. Schmutzler, Julian Peto, Irene L. Andrulis, Chenjie Zeng, Kenneth Muir, Peter Schürmann, Saila Kauppila, Banu Arun, Jane Carpenter, Jeffrey N. Weitzel, Yael Laitman, Susan M. Domchek, Robert Winqvist, Caroline Baynes, Brita Arver, Marc Tischkowitz, Kamila Czene, Keitaro Matsuo, Barbara Burwinkel, Miriam Dwek, Kim De Leeneer, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Peter A. Fasching, Bernd Dworniczak, Susan J. Ramus, Lesley McGuffog, Andrea Gehrig, Michael J. Kerin, Thomas Hansen, Francesca Damiola, John L. Hopper, Loic Le Marchand, Peter J. Hulick, Annika Lindblom, Emily Hallberg, Miguel de la Hoya, Gaetana Gambino, Martine Dumont, Susan L. Slager, Bernardo Bonanni, Bent Ejlertsen, Norhashimah Hassan, Sue Healey, Orland Diez, Mary B. Daly, Carolyn B. Hendricks, Artitaya Lophatananon, Annelie Liljegren, Steven N. Hart, Jan Lubinski, Natalia Bogdanova, Drakoulis Yannoukakos, Steve Ellis, Silje Nord, Hiltrud Brauch, Gad Rennert, Conxi Lázaro, Daniel C. Tessier, Paolo Radice, Dominique Stoppa-Lyonnet, Nadine Tung, Andrew K. Godwin, Suleeporn Sangrajrang, Karoline Kuchenbaecker, Javier Benitez, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, Department of Oncology, Department of Obstetrics and Gynecology, School of Medicine / Clinical Medicine, Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Tischkowitz, Marc [0000-0002-7880-0628], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Clinical Genetics, Medical Oncology, and Obstetrics & Gynecology
Subjects: 0301 basic medicine, Fine-scale mapping, Genome-wide association study, HORMONE-RELATED PROTEIN, Epigenesis, Genetic, Breast cancer, Medizinische Fakultät, Databases, Genetic, Genotype, BRCA2 MUTATION CARRIERS, Odds Ratio, Medicine and Health Sciences, Pair 12, Medicine, Genetic risk factor, Promoter Regions, Genetic, Medicine(all), Genetics, BRCA1 Protein, PTHLH-CCDC91, Chromosome Mapping, LOCALIZATION, Single Nucleotide, PTHLH, 3. Good health, Enhancer Elements, Genetic, Population Surveillance, Female, Medical Genetics, BRAC1 mutation carriers, CCDC91, Alleles, Breast Neoplasms, Case-Control Studies, Computational Biology, European Continental Ancestry Group, Haplotypes, Heterozygote, Humans, Mutation, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, Chromosomes, Human, Pair 12, Genetic Predisposition to Disease, Genome-Wide Association Study, Human, Research Article, EXPRESSION, Enhancer Elements, SUSCEPTIBILITY LOCI, 3122 Cancers, Single-nucleotide polymorphism, Chromosomes, White People, OVARIAN-CANCER, Càncer de mama, Promoter Regions, Databases, 03 medical and health sciences, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, Genetic, Journal Article, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Medicinsk genetik, Genetic association, Cancer och onkologi, business.industry, Haplotype, Case-control study, Biology and Life Sciences, Odds ratio, medicine.disease, ENHANCERS, 030104 developmental biology, Cancer and Oncology, METASTASIS, 3111 Biomedicine, GENETIC MODIFIERS, business, Genètica, Epigenesis
Abstract: Article, Background Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; P = 3 × 10-9), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; P = 2 × 10-4) identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P, published version, peerReviewed
Published: 2016

37. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Author: Agnieszka Dansonka-Mieszkowska, Angela Brooks-Wilson, Ingo B. Runnebaum, Kenneth Offit, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Christine Maugard, Marco Montagna, Annette Fontaine, Janusz Menkiszak, Robert Winqvist, Pascal Guénel, Rosalind Glasspool, Usha Menon, Daniel Barrowdale, Elinor J. Sawyer, Anna Jakubowska, Paul D.P. Pharoah, Martha J. Shrubsole, Lambertus A. Kiemeney, Camilla Krakstad, Dong Liang, Minouk J. Schoemaker, Judith S. Brand, Joseph Vijai, Marc T. Goodman, Thomas A. Sellers, David Van Den Berg, Celeste Leigh Pearce, Alice S. Whittemore, Irene L. Andrulis, Radka Platte, Kunle Odunsi, Orland Diez, Estrid Høgdall, Brooke L. Fridley, C. J. van Asperen, Mary Anne Rossing, Vessela N. Kristensen, Jonathan Tyrer, Tara M. Friebel, Douglas F. Easton, Per Hall, Mads Thomassen, Christine Walsh, Thilo Dörk, Louise A. Brinton, Keith Humphreys, Douglas A. Levine, Allison F. Vitonis, Anna H. Wu, Hermann Brenner, Maria Bisogna, Joellen M. Schildkraut, Maria A. Caligo, Jonine D. Figueroa, Lynne R. Wilkens, Grace Friel, Michael G. Schrauder, Evgeny N. Imyanitov, Sune F. Nielsen, Sylvie Mazoyer, Diana Eccles, Andrew Berchuck, Sara Margolin, Mitul Shah, Matthias W. Beckmann, Elizabeth M. Poole, Gad Rennert, Arif B. Ekici, Elisa Alducci, Bjarni A. Agnarsson, Linda S. Cook, Javier Benitez, Paolo Peterlongo, Natalia Antonenkova, Annika Lindblom, Patrick Neven, Julia A. Knight, Alan Ashworth, Matti A. Rookus, Frans B. L. Hogervorst, Daniela Zaffaroni, Banu Arun, Sue Healey, Robert P. Edwards, Susanne K. Kjaer, Laura J. van't Veer, John W.M. Martens, Christa Stegmaier, Claudine Isaacs, Daniel W. Cramer, Lars Beckmann, Liisa M. Pelttari, Dieter Flesch-Janys, Irene Orlow, Atocha Romero, Diana Torres, Marjanka K. Schmidt, Simon S. Cross, Alison M. Dunning, Rosemary L. Balleine, Sandra L. Halverson, Benoit Beuselinck, Melissa C. Larson, Senno Verhoef, Jirong Long, Angela Cox, Maartje J. Hooning, Bruce Poppe, Katarzyna Jaworska, Jolanta Kupryjanczyk, Nicolas Wentzensen, Gustavo C. Rodriguez, Tanja Pejovic, Roberta B. Ness, James Paul, Dominique Stoppa-Lyonnet, Nadine Tung, Gianluca Severi, Malcolm C. Pike, Hoda Anton-Culver, Ans M.W. van den Ouweland, Mark E. Robson, Roger L. Milne, Jan C. Oosterwijk, Laima Tihomirova, Helen Tsimiklis, Pierre Laurent-Puig, Florian Heitz, Beth Y. Karlan, Ian Tomlinson, Thérèse Truong, Bernardo Bonanni, Frederik Marmé, Qin Wang, Conxi Lázaro, Volker Arndt, Antoinette Hollestelle, Jacek Gronwald, M. Pilar Zamora, Barbara Wappenschmidt, Maren Weischer, Veli-Matti Kosma, Giulietta Scuvera, Jenny Lester, Andreas Berger, Stephen J. Chanock, Line Bjørge, Anthony J. Swerdlow, Andrew K. Godwin, Mervi Grip, Amanda E. Toland, Anna Marie Mulligan, Noralane M. Lindor, Paolo Radice, Bent Ejlertsen, Frederieke H. van der Baan, Lothar Haeberle, Valerie McGuire, Kamila Czene, Rob A. E. M. Tollenaar, Maria Soller, Katherine L. Nathanson, Sandrina Lambrechts, Susan J. Ramus, Anja Rudolph, Penny Soucy, Caroline Weltens, Hiltrud Brauch, Olivia Fletcher, Sara H. Olson, Yael Laitman, Marion Piedmonte, Arto Mannermaa, Agnieszka Budzilowska, Olga M. Sinilnikova, Christian F. Singer, Cezary Cybulski, Weiva Sieh, Ed Dicks, Elizabeth J. van Rensburg, Isabel dos Santos Silva, Hans Ehrencrona, Timothy R. Rebbeck, Jaana M. Hartikainen, Sandra Orsulic, Jingmei Li, Carmel Apicella, Anna deFazio, Ian G. Campbell, Ignace Vergote, Rita K. Schmutzler, Fredrick R. Schumacher, Julian Peto, Nadeem Siddiqui, Brian E. Henderson, Starr R. Guzman, Maria Kabisch, John L. Hopper, Arto Leminen, Jeffrey N. Weitzel, Honglin Song, J. Margriet Collée, Ingvild L. Tangen, Børge G. Nordestgaard, Antonis C. Antoniou, Lara Sucheston, Helena C. van Doorn, Lídia Feliubadaló, Leon F.A.G. Massuger, Iain A. McNeish, Nichola Johnson, Simon A. Gayther, Jennifer A. Doherty, Anders Bojesen, Gord Glendon, Yukie Bean, Celine M. Vachon, Barbara Burwinkel, Edith Olah, Shan Wang-Gohrke, Brita Arver, Marc Tischkowitz, Arja Jukkola-Vuorinen, Martin Gore, Vesa Kataja, Nicola Miller, Pamela J. Thompson, Malcolm W.R. Reed, Michelle A.T. Hildebrandt, Ritu Salani, Janet E. Olson, Catriona McLean, Cecilia M. Dorfling, Georgia Chenevix-Trench, Frederique Mariette, Laura Ottini, Fergus J. Couch, Linda E. Kelemen, Nhu D. Le, Michael J. Kerin, Claus Høgdall, Miguel de la Hoya, Jonathan Carter, Mercedes Durán, Inge Søkilde Pedersen, Julie M. Cunningham, Manjeet K. Bolla, Galina Lurie, Loic Le Marchand, Ute Hamann, Muy-Kheng Tea, Karoline Kuchenbaecker, Irene Konstantopoulou, Thomas Hansen, Francesca Damiola, Stefano Fortuzzi, Shelley S. Tworoger, Mikael Eriksson, Carl Blomqvist, Joan Brunet, Allan Jensen, Karen Lu, Elisa V. Bandera, Anne M. van Altena, Anne-Marie Gerdes, Lene Lundvall, Susan L. Neuhausen, Wei Zheng, Ana Osorio, Fiona Bruinsma, Hannah P. Yang, Graham G. Giles, Christoph Engel, Nick Orr, Harvey A. Risch, Jan Lubinski, Jacoba P. Knol-Bout, Phuong L. Mai, Martine Dumont, Xifeng Wu, Christof Sohn, Noah D. Kauff, Kristiina Aittomäki, Natalia Bogdanova, Alexander Hein, Francesmary Modugno, Heli Nevanlinna, Helga B. Salvesen, Adriana Lasa, Daphne Gschwantler Kaulich, Dominiek Smeets, Jenny Permuth-Wey, Josef Herzog, Catherine M. Phelan, Clareann H. Bunker, Steve Ellis, Christopher A. Haiman, Jolanta Lissowska, Judy Garber, Joanna Plisiecka-Halasa, Robert A. Vierkant, Steven A. Narod, Mark H. Greene, Florence Menegaux, Norbert Arnold, Primitiva Menéndez, Robert L. Nussbaum, Katja K.H. Aben, Andreas Schneeweiss, Katri Pylkäs, Els Van Nieuwenhuysen, Tomasz Huzarski, Joe Dennis, Susan M. Domchek, Andreas du Bois, Aleksandra Gentry-Maharaj, Florentia Fostira, Mary Beth Terry, Jenny Chang-Claude, Eitan Friedman, Argyrios Ziogas, Hatef Darabi, Kathleen Claes, Ellen L. Goode, Olufunmilayo I. Olopade, Stig E. Bojesen, Jo Perkins, Raanan Berger, Sharon E. Johnatty, Taru A. Muranen, Montserrat Garcia-Closas, Uffe Birk Jensen, Thomas Brüning, Heiko Müller, Debra Frost, Peter A. Fasching, Lesley McGuffog, Diether Lambrechts, Kelly-Anne Phillips, Caroline M. Seynaeve, Kathryn L. Terry, Ira Schwaab, Ralf Bützow, Manuel R. Teixeira, Joseph H. Rothstein, Bernard Peissel, Anna von Wachenfeldt, Saundra S. Buys, Peter Devilee, Alfons Meindl, Laura Baglietto, Kirsten B. Moysich, Arjen R. Mensenkamp, Philipp Harter, Jacques Simard, Generalitat de Catalunya, Ministerio de Ciencia e Innovación (España), Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, National Institutes of Health (US), Wellcome Trust, European Commission, National Cancer Institute (US), Medical Oncology, Clinical Genetics, Erasmus MC other, Pediatric Surgery, Pathology, and Neurology
Subjects: 0301 basic medicine, Oncology, endocrine system diseases, Endometriosis, Breast cancer, Clinical outcome, Genetic association, KRAS variant, Ovarian cancer, Genome-wide association study, Carcinoma, Ovarian Epithelial, medicine.disease_cause, Prostate, Brjóstakrabbamein, Clinical outcomes, Genotype, Obstetrics and Gynaecology, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], PROSTATE, Neoplasms, Glandular and Epithelial, skin and connective tissue diseases, RISK, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Obstetrics and Gynecology, WOMEN, female genital diseases and pregnancy complications, 3. Good health, medicine.anatomical_structure, Treatment Outcome, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, KRAS, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Breast Neoplasms, Article, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Carcinoma, Humans, GENOME-WIDE ASSOCIATION, Genetic Association Studies, POLYMORPHISMS, Krabbamein, MICRORNA-BINDING-SITE, IDENTIFICATION, business.industry, ENDOMETRIOSIS, Arfgengi, medicine.disease, 030104 developmental biology, PTT12, Eggjastokkar, business
Abstract: Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, and Consortium of Modifiers of BRCA1 and BRCA2: et al., [Objective]: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. [Methods]: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). [Results]: We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. [Conclusions]: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers., The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 — HEALTH-F2-2009-223175). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). Funding for the project was provided by the Wellcome Trust under award 076113. This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrileña Foundation (FMMA) and SAF2010-20493. Was supported by a grant RD12/00369/0006 and 12/00539 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. Contract grant sponsor: Asociación Española Contra el Cáncer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. Contract grant numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285 and 2009SGR290.
Published: 2016

38. Corrigendum: Common variants at 19p13 are associated with susceptibility to ovarian cancer

Author: Falk Thiel, Simon A. Gayther, Susan Kruger-Kjaer, Matthias Dürst, Robert M Brown, Thilo Doerk, Martin Gore, James M. Flanagan, Ian Tomlinson, Stephen J. Chanock, Thorunn Rafnar, Susan J. Ramus, Brooke L. Fridley, Jonathan Beesley, Jennifer A. Doherty, Tanya Sher, Jan Lubinski, Ya Yu Tsai, Wendy Brewster, Edwin S. Iversen, Evelyn Despierre, Mary Anne Rossing, Jenny Gross, Stanley B. Kaye, Galina Lurie, Natalia Bogdanova, Douglas A. Levine, Peter A. Fasching, Honglin Song, Patrick Sulem, Anna H. Wu, Angela Brooks-Wilson, Ingo B. Runnebaum, Estrid Høgdall, Natalia Antonenkova, Robert P. Edwards, Kara L. Cushing-Haugen, Francesmary Modugno, Ignace Vergote, Søren Besenbacher, Matthias W. Beckmann, Michael J. Birrer, Anna Jakubowska, Paul D.P. Pharoah, Kirsten B. Moyisch, David Van Den Berg, Steven A. Narod, Anne M. van Altena, Lambertus A. Kiemeney, Andrew Berchuck, Daniel W. Cramer, Arto Leminen, Peter Hillemanns, Alice S. Whittemore, Kunle Odunsi, Beth Y. Karlan, Douglas F. Easton, Diether Lambrechts, T A Sellers, Joellen M. Schildkraut, Heli Nevanlinna, Jolanta Lissowska, Kathryn L. Terry, Robert A. Vierkant, Ralf Bützow, Tuomas Heikkinenen, Jan Blaeker, Katja K.H. Aben, Krzysztof Mędrek, Georgia Chenevix-Trench, Weiva Sieh, Leon F.A.G. Massuger, Maria Notaridou, Linda S. Cook, Montserrat Garcia-Closas, Julie A. Baker, Kari Stefansson, Frédéric Amant, Michael E. Carney, Rachel T. Palmieri, Jacek Gronwald, Catherine M. Phelan, Chu Chen, Claus Høgdall, Pamela J. Thompson, Arif B. Ekici, Xiaoqing Chen, Eva Wozniak, Argyrios Ziogas, Aleksandra Gentry-Maharaj, Daniel Paik, Valerie McGuire, Marc T. Goodman, Ian G. Campbell, Hoda Anton-Culver, Shan Wang-Gohrke, Linda E. Kelemen, Jonathan Tyrer, Julie M. Cunningham, Celeste Leigh Pearce, Penelope M. Webb, Rebecca Hein, Dena G. Hernandez, Kelly L. Bolton, Chris Jones, Patricia G. Moorman, Joanne B. Weidhaas, Nhu D. Le, Daniel O. Stram, Roberta B. Ness, James Paul, Hanna P. Yang, Richard S. Houlston, Ellen L. Goode, Sharon E. Johnatty, and Jenny Chang-Claude
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Genotype, MEDLINE, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Internal medicine, Genetics, medicine, Biomarkers, Tumor, Tumor Cells, Cultured, Humans, Genetic Predisposition to Disease, Adaptor Proteins, Signal Transducing, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, Genome, Human, Published Erratum, Gene Expression Profiling, Ovary, Middle Aged, medicine.disease, Adenocarcinoma, Mucinous, Cystadenocarcinoma, Serous, Endometrial Neoplasms, 030104 developmental biology, Case-Control Studies, Female, Ovarian cancer, Chromosomes, Human, Pair 19, Adenocarcinoma, Clear Cell, Genome-Wide Association Study
Abstract: Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 × 10⁻⁴ and P = 6 × 10⁻⁴, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 × 10⁻⁹ and P = 4 × 10⁻¹¹, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.
Published: 2016

39. Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study

Author: Liisa M. Pelttari, Joseph L. Kelley, Adriaan Vanderstichele, Jue-Sheng Ong, Jonathan Tyrer, Linda S. Cook, Sara H. Olson, Agnieszka Dansonka-Mieszkowska, Ellen L. Goode, Fiona Bruinsma, Roberta B. Ness, Daniel W. Cramer, Francesmary Modugno, Penelope M. Webb, C. Blake Gilks, Britton Trabert, Jacek Gronwald, Diana Eccles, Georgia Chenevix-Trench, Fanny Dao, Michelle A.T. Hildebrandt, Graham G. Giles, Gabriel Cuellar-Partida, Julie M. Cunningham, Puya Gharahkhani, Celeste Leigh Pearce, Usha Menon, Maria Bisogna, Estrid Høgdall, Shelley S. Tworoger, Allan Jensen, Alexander Hein, Matthias W. Beckmann, Anna Jakubowska, Paul D.P. Pharoah, Xifeng Wu, Valerie McGuire, Dong Liang, Robert P. Edwards, Joellen M. Schildkraut, Catherine M. Phelan, John R. McLaughlin, Arto Leminen, Heli Nevanlinna, Stacey A. Missmer, Brooke L. Fridley, Angela Brooks-Wilson, Ingo B. Runnebaum, Lambertus A. Kiemeney, Elizabeth M. Poole, Yi-chen Lu, Jolanta Lissowska, Jennifer A. Doherty, Ian G. Campbell, Susanne K. Kjaer, Mary Anne Rossing, Stuart MacGregor, Argyrios Ziogas, Thilo Dörk, Stefanie Burghaus, Douglas A. Levine, Claus Høgdall, Jolanta Kupryjanczyk, Kirsten B. Moysich, Nicolas Wentzensen, Katja K.H. Aben, Shan Wang-Gohrke, Katharina Bischof, Reidun K. Kopperud, Alice S. Whittemore, Hoda Anton-Culver, Ursula Eilber, Karen Lu, Elisa V. Bandera, Line Bjørge, Simon A. Gayther, Rikki Cannioto, Honglin Song, Els Van Nieuwenhuysen, Susan J. Ramus, Louise A. Brinton, Steven A. Narod, Meir J. Stampfer, Anja Rudolph, Ignace Vergote, Matthias Dürst, Andrew Berchuck, Peter Hillemanns, Rachel E. Neale, Aleksandra Gentry-Maharaj, Lukasz Szafron, Harvey A. Risch, Jenny Chang-Claude, Terry K. Morgan, Marc T. Goodman, Natalia Bogdanova, Helga B. Salvesen, Weiva Sieh, Ralf Bützow, Peter A. Fasching, Joseph H. Rothstein, Agnieszka Timorek, Nhu D. Le, Diether Lambrechts, Anna H. Wu, Natalia Antonenkova, Stacey J. Winham, Jan Lubinski, Kathryn L. Terry, Tomasz Kluz, and Leon F.A.G. Massuger
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, Single-nucleotide polymorphism, Australian Ovarian Cancer Study, Carcinoma, Ovarian Epithelial, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Mendelian Randomization, Risk Factors, Internal medicine, Mendelian randomization, medicine, Vitamin D and neurology, Odds Ratio, Humans, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial, Vitamin D, Ovarian Neoplasms, Cancer prevention, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], business.industry, Confounding, Statistics, Cancer, General Medicine, Odds ratio, Mendelian Randomization Analysis, medicine.disease, 3. Good health, 030104 developmental biology, Endocrinology, 030220 oncology & carcinogenesis, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Public Health and Health Services, Female, business, Ovarian cancer
Abstract: Contains fulltext : 171904.pdf (Publisher’s version ) (Closed access) BACKGROUND: In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer. METHODS: We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases). RESULTS: The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01). CONCLUSIONS: Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.
Published: 2016

40. Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)

Author: Steven A. Narod, Beata Spiewankiewicz, Usha Menon, Tanja Pejovic, Dong Liang, Lynne R. Wilkens, Diana Eccles, Claus Høgdall, Florian Heitz, Beth Y. Karlan, John R. McLaughlin, Xiao-Ou Shu, Jennifer A. Doherty, Marc T. Goodman, Yu-Tang Gao, Brooke L. Fridley, Matthias W. Beckmann, Satoyo Hosono, Mary Anne Rossing, Elizabeth M. Poole, Thilo Dörk, Roger L. Milne, Douglas A. Levine, Arif B. Ekici, Francesmary Modugno, Hanis Nazihah Hasmad, Evelyn Despierre, Harvey A. Risch, Michelle A.T. Hildebrandt, Jenny Lester, Argyrios Ziogas, Arto Leminen, Sara H. Olson, Kate Lawrenson, Sandra Orsulic, Nadeem Siddiqui, Weiva Sieh, Ganna Chornokur, Ernest K. Amankwah, Natalia Bogdanova, Liisa M. Pelttari, Nhu D. Le, Lene Lundvall, Kirsten B. Moysich, Robert A. Vierkant, Helga B. Salvesen, Douglas F. Easton, Yin Ling Woo, Lotte Ansgaard Thomsen, Boon Kiong Lim, Philipp Harter, Hannah P. Yang, Graham G. Giles, Andrew Berchuck, Heather S.L. Jim, Anna H. Wu, Christine Walsh, Zhihua Chen, Alice S. Whittemore, Louise A. Brinton, Anne M. van Altena, Alice W. Lee, Fiona Bruinsma, Iwona K. Rzepecka, Natalia Antonenkova, Melissa Kellar, Jonathan Tyrer, Peter Hillemanns, Kunle Odunsi, Joe Dennis, Heli Nevanlinna, Alexander Hein, Catherine M. Phelan, Xifeng Wu, Jolanta Lissowska, Angela Brooks-Wilson, Ingo B. Runnebaum, Roberta B. Ness, James Paul, Linda S. Cook, Jacek Gronwald, Katja K.H. Aben, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, Linda E. Kelemen, Sandrina Lambrechts, Jan Lubinski, Leon F.A.G. Massuger, Karen Carty, Matthias Dürst, Ursula Eilber, Simon A. Gayther, Karen Lu, Bu-Tian Ji, Elisa V. Bandera, Shashi Lele, Keitaro Matsuo, Maria Bisogna, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Susan J. Ramus, Alvaro N.A. Monteiro, Edwin S. Iversen, Robert P. Edwards, Diether Lambrechts, Ellen L. Goode, Pamela J. Thompson, Ralf Bützow, Clareann H. Bunker, Jennifer Permuth-Wey, Anja Rudolph, Joseph H. Rothstein, Kathryn L. Terry, Ira Schwaab, Andreas du Bois, Aleksandra Gentry-Maharaj, Jolanta Kupryjanczyk, Nicolas Wentzensen, Ignace Vergote, Valerie McGuire, Jenny Chang-Claude, Ingvild L. Tangen, Ian G. Campbell, Daniel W. Cramer, Shan Wang-Gohrke, Peter A. Fasching, Rosalind Glasspool, Camilla Krakstad, Hoda Anton-Culver, Eva S. Schernhammer, Thomas A. Sellers, Lara E. Sucheston-Campbell, Estrid Høgdall, Yurii B. Shvetsov, Joellen M. Schildkraut, Honglin Song, Julie M. Cunningham, Shelley S. Tworoger, Allan Jensen, Ian McNeish, Wei Zheng, Barry P. Rosen, Malcolm C. Pike, Line Bjørge, Cezary Cybulski, Celeste Leigh Pearce, Kristine G. Wicklund, Soo-Hwang Teo, Susanne K. Kjaer, Hui-Yi Lin, Irene Orlow, Yukie Bean, Ann Y. Chen, and Rachel Palmieri Weber
Subjects: endocrine system, 0303 health sciences, media_common.quotation_subject, Single-nucleotide polymorphism, Biology, medicine.disease, Bioinformatics, Article, 03 medical and health sciences, PER3, 0302 clinical medicine, CSNK1E, 030220 oncology & carcinogenesis, Genotype, Genetic variation, Cancer research, medicine, Circadian rhythm, Ovarian cancer, Ovulation, 030304 developmental biology, media_common
Abstract: Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10(-4)]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways. ispartof: Journal of Genetics and Genome Research vol:2 issue:2 pages:017- ispartof: location:United States status: published
Published: 2015

41. Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium

Author: Peter Hillemanns, Mark E. Robson, Roger L. Milne, Amanda B. Spurdle, Rob A. E. M. Tollenaar, Federik Marme, Michael Bremer, Jan Lubinski, Linda Titus-Ernstoff, Kamila Czene, Stephen J. Chanock, Mervi Grip, Graham G. Giles, Penny Webb, G. Chenevix-Trench, Natalia Bogdanova, John L. Hopper, Frances P. O'Malley, Arto Mannermaa, Mark E. Sherman, Chen-Yang Shen, Suleeporn Sangrajrang, Julian Peto, Irene L. Andrulis, Yuri I. Rogov, Annika Lindblom, Børge G. Nordestgaard, James McKay, Barbara Burwinkel, M. Pilar Zamora, José Ignacio Arias, Beate Pesch, Vijai Joseph, Shamil Hanafievich Gantcev, Fergus J. Couch, Dong Young Noh, Betül T. Yesilyurt, Jenny Chang-Claude, Ute Hamann, Vesa Kataja, Sara Margolin, Thilo Dörk, Katarzyna Jaworska, Yon Ko, Nichola Johnson, Hiltrud Brauch, Matthias W. Beckmann, Heli Nevanlinna, Malcolm W.R. Reed, Melissa C. Southey, Arif B. Ekici, Jolanta Lissowska, Isabel dos Santos Silva, Johann H. Karstens, Robert Winqvist, Shian Ling Ding, Stig E. Bojesen, Ian Tomlinson, Anna Marie Mulligan, Montserrat Garcia-Closas, Volker Harth, Katarzyna Durda, Valerie Gaborieau, Tuomas Heikkinen, Thomas Brüning, Mia M. Gaudet, Monica Barile, Sylvia Rabstein, Christina Justenhoven, Anna Jakubowska, Paul D.P. Pharoah, Jonathan Beesley, Hermann Brenner, Elza Khusnutdinova, Heiko Müller, Jyh Cherng Yu, Adam M. Lee, Paolo Peterlongo, Clare Turnbull, Doug Easton, Radka Platte, Keun-Young Yoo, J. Margriet Collée, Paolo Radice, Laura Baglietto, Sei Hyun Ahn, Paul Brennan, Olivia Fletcher, Fleur Hammet, Ans M.W. van den Ouweland, Catriona Maclean, Carl Blomqvist, Sheila Seal, Peter Schürmann, Natalia Antonenkova, Katri Pylkäs, Angela Cox, Kenneth Offit, Huan Ming Hsu, Arja Jukkola-Vuorinen, Maartje J. Hooning, Peter A. Fasching, Alison M. Dunning, Nick Orr, Volker Arndt, Javier Benitez, Diether Lambrechts, Robert B. Diasio, Manjeet K. Humphreys, Ian W. Brock, Marjanka K. Schmidt, Per Hall, Hoda Anton-Culver, Anthony J. Swerdlow, Jonine D. Figueroa, Julia A. Knight, Ylermi Soini, Alan Ashworth, Veli-Matti Kosma, Anna deFazio, Reiner Strick, Darya Prokofieva, Shan Wang-Gohrke, Polly A. Newcomb, Dorota M. Gertig, Henrik Flyger, David D.L. Bowtell, Laura J. van't Veer, John W.M. Martens, Carmel Apicella, Anthony Renwick, Andreas Schneeweiss, Michael J. Kerin, Christian Baisch, Xianshu Wang, Kathleen Egan, Argyrios Ziogas, A. Green, Marina Bermisheva, Christof Sohn, Stéphanie Peeters, Daehee Kang, Rebecca Hein, Nazneen Rahman, Annegien Broeks, Georgia Chenevix-Trench, Elinor J. Sawyer, Louise A. Brinton, Michael Jones, Xiaoqing Chen, Kristiina Aittomäki, Esther M. John, Siranoush Manoukian, Hand Peter Fischer, Amy Trentham-Dietz, Simon S. Cross, Marie Rose Chrisiaens, Gianluca Severi, Medical Oncology, and Clinical Genetics
Subjects: Oncology, Receptor, ErbB-2, 6q25.1, Estrogen receptor, Genome-wide association study, Alleles, Breast Neoplasms, Case-Control Studies, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 14, Confidence Intervals, DNA-Binding Proteins, Female, Genetic Heterogeneity, Genetic Predisposition to Disease, Humans, Odds Ratio, Polymorphism, Single Nucleotide, Receptors, Estrogen, Receptors, Progesterone, Risk Factors, Genome-Wide Association Study, Molecular Biology, Genetics, Genetics (clinical), brca1, 0302 clinical medicine, ErbB-2, Receptors, glucose, mutation carriers, Progesterone, 0303 health sciences, Association Studies Articles, General Medicine, Single Nucleotide, 3. Good health, 030220 oncology & carcinogenesis, Pair 1, metaanalysis, Human, Receptor, medicine.medical_specialty, Single-nucleotide polymorphism, Biology, Chromosomes, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, SNP, Polymorphism, 030304 developmental biology, Genetic heterogeneity, Pair 14, Case-control study, Odds ratio, confer susceptibility, medicine.disease, Estrogen, susceptibility loci, Immunology, genome-wide association, polymorphisms
Abstract: A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2) = 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98-1.07, case-only P-heterogeneity = 7.6 x 10 25]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P = 6.7 x 10 23) and lobular histology (case-only P = 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer.
Published: 2011

42. Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2

Author: Eugenia E. Calle, Alice J. Sigurdson, Susan E. Hankinson, Alfons Meindl, Hoda Anton-Culver, Letitia D. Smith, Richard van Hien, R.A.E.M. Tollenaar, Louise A. Brinton, Veli-Matti Kosma, Stephen J. Chanock, Laura Baglietto, Anna González-Neira, Jonathan J. Morrison, Olivia Fletcher, Radka Platte, Michele M. Doody, Sei Hyun Ahn, Douglas F. Easton, Henrik Flyger, Merethe Kumle, Georgia Chenevix-Trench, Chen-Yang Shen, Beata Peplonska, Kamila Czene, J. David Curb, Christi J. van Asperen, Per Hall, Natalia Antonenkova, Irene L. Andrulis, Mieke Schutte, Claus R. Bartram, John L. Hopper, Daehee Kang, Amanda B. Spurdle, Peter Kraft, David J. Hunter, Kristiina Aittomäki, Bruce H. Alexander, Bruce A.J. Ponder, Malcolm W.R. Reed, Julia A. Knight, Christine D. Berg, Melissa C. Southey, S. A. Fedorova, Giu Cheng Hsu, Catherine A. McCarty, Arto Mannermaa, Rebecca Hein, Gianluca Severi, Peter Schürmann, Diana Eccles, Argyrios Ziogas, Shou Tung Chen, Ian W. Brock, Fergus J. Couch, Garnet L. Anderson, Ellen L. Goode, Nichola Johnson, Sara Margolin, Paul D.P. Pharoah, Annika Lindblom, W. Ryan Diver, Ute Hamann, Robert N. Hoover, Michael R. Stratton, Iosif V. Zalutsky, Yuqing Li, Sten Cornelissen, Natalia Bogdanova, Caroline Seynaeve, Rita K. Schmutzler, Julian Peto, Børge G. Nordestgaard, Robert Luben, Aleksandar Rajkovic, Stig E. Bojesen, Heather Spencer Feigelson, Saundra S. Buys, Marina Bermisheva, Barbara Burwinkel, Peter Devilee, Isabel dos Santos Silva, Jonathan Beesley, Thilo Dörk, Gilles Thomas, Lars J. Vatten, Tuomas Heikkinen, Ross L. Prentice, David G. Cox, D. Gareth Evans, Manjeet K. Humphreys, Marjanka K. Schmidt, Shan Wang-Gohrke, Melanie Maranian, Shahana Ahmed, Janet E. Olson, Dallas R. English, Maya Ghoussaini, Heli Nevanlinna, Dong Young Noh, Jolanta Lissowska, Graeme Elliott, Vesa Kataja, Nazneen Rahman, Peter Hillemanns, Annegien Broeks, Roger L. Milne, Johann H. Karstens, Christina Justenhoven, Montserrat Garcia-Closas, Karen A. Pooley, Zachary S. Fredericksen, Jyh Cherng Yu, Angela Cox, Maartje J. Hooning, Alison M. Dunning, Ans M.W. van den Ouweland, Hiltrud Brauch, Regina G. Ziegler, Jianjun Liu, Parveen Bhatti, Kristian Hveem, Kevin B. Jacobs, Catherine S. Healey, Jenny Chang-Claude, Michael J. Thun, Rogier A. Oldenburg, Elza Khusnutdinova, Xianshu Wang, Keun-Young Yoo, Carl Blomqvist, Gloria Ribas, Graham G. Giles, and Javier Benitez
Subjects: Genotype, Breast Neoplasms, Genome-wide association study, Biology, Article, Chromosomes, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Chromosome Mapping, Chromosomes, Human, Pair 17, Chromosomes, Human, Pair 3, Disease Susceptibility, Female, Genetic Predisposition to Disease, Genome, Human, Humans, Genetics, Genetic predisposition, medicine, 030304 developmental biology, Genetic association, 0303 health sciences, Genome, Pair 17, Cancer, medicine.disease, 3. Good health, TOX3, Pair 3, 030220 oncology & carcinogenesis, Breast disease, Human
Abstract: Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08-1.13, P = 4.1 x 10(-23)) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92-0.97, P = 1.4 x 10(-8)). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q.
Published: 2009

43. Risk of Estrogen Receptor-Positive and -Negative Breast Cancer and Single-Nucleotide Polymorphism 2q35-rs13387042

Author: Gianluca Severi, Hoda Anton-Culver, Veli-Matti Kosma, Peter Hillemanns, Louise A. Brinton, Douglas F. Easton, Georgia Chenevix-Trench, Roger L. Milne, Hui-Chun Wang, Chen-Yang Shen, Christie J. van Asperen, Hiltrud Brauch, M. Pilar Zamora, Rob A. E. M. Tollenaar, Heli Nevanlinna, Kristiina Aittomäki, Olivia Fletcher, Melissa C. Southey, Malcolm W.R. Reed, Jonathan Beesley, Jolanta Lissowska, Isabel dos Santos Silva, Nichola Johnson, Stig E. Bojesen, Per Hall, José Ignacio Arias, Tuomas Heikkinen, Janet E. Olson, Ian W. Brock, Clare Turnbull, Tatjana Nikolaeva, Dong-Young Noh, Yuqing Li, Paul D.P. Pharoah, Michael Bremer, Matthias W. Beckmann, Alison M. Dunning, Kamila Czene, Radka Platte, Keun-Young Yoo, Claus R. Bartram, Letitia D. Smith, John L. Hopper, kConFab Investigators, Natalia Antonenkova, Natalia Bogdanova, Stephen J. Chanock, Graeme Elliott, Vesa Kataja, Christina Justenhoven, Zachary S. Fredericksen, Thilo Dörk, Daehee Kang, Reiner Strick, Iosif V. Zalutsky, Shan Wang-Gohrke, Melanie Maranian, Shahana Ahmed, Peter Schürmann, Angela Cox, Arif B. Ekici, Sou-Tong Chen, Fergus J. Couch, Argyrios Ziogas, Jonathan J. Morrison, Jenny Chang-Claude, Yon-Dschun Ko, Henrik Flyger, Jianjun Liu, Peter A. Fasching, Caroline Seynaeve, Marina Bermisheva, Dallas R. English, Graham G. Giles, Xianshu Wang, Montserrat Garcia-Closas, Jyh-Cherng Yu, Nazneen Rahman, Elza Khusnutdinova, Rita K. Schmutzler, Julian Peto, Børge G. Nordestgaard, Carl Blomqvist, Barbara Burwinkel, Anthony Renwick, Manjeet K. Humphreys, Amanda B. Spurdle, Arto Mannermaa, Susanne Haas, Sarah Hines, Peter Devilee, Alfons Meindl, Laura Baglietto, Javier Benitez, Hematology, Medical Oncology, and Clinical Genetics
Subjects: Cancer Research, Estrogen receptor, Noninfiltrating, Linkage Disequilibrium, 0302 clinical medicine, Gene Frequency, Neoplasms, Ductal, Receptors, Odds Ratio, Breast, Progesterone, 0303 health sciences, Tumor, Medicine (all), Carcinoma, Ductal, Breast, Confounding Factors, Epidemiologic, Articles, Single Nucleotide, Middle Aged, Control subjects, Prognosis, 3. Good health, Receptors, Estrogen, Oncology, 030220 oncology & carcinogenesis, Female, Breast disease, Receptors, Progesterone, Adult, Asian Continental Ancestry Group, medicine.medical_specialty, Neoplasms, Hormone-Dependent, Genotype, Intraductal, European Continental Ancestry Group, Single-nucleotide polymorphism, Breast Neoplasms, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Breast cancer, European origin, Asian People, SDG 3 - Good Health and Well-being, Predictive Value of Tests, Internal medicine, medicine, Biomarkers, Tumor, Confidence Intervals, Humans, Genetic Predisposition to Disease, Hormone-Dependent, Polymorphism, 030304 developmental biology, Aged, business.industry, Carcinoma, Odds ratio, medicine.disease, Carcinoma, Intraductal, Noninfiltrating, Case-Control Studies, Confounding Factors (Epidemiology), Estrogen, Endocrinology, Multicenter study, business, Humanities, Biomarkers
Abstract: Background: A recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)–positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium. Methods: 2q35-rs13387042 SNP was genotyped for 31 510 women with invasive breast cancer, 1101 women with ductal carcinoma in situ, and 35 969 female control subjects from 25 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity in odds ratios by each of age, ethnicity, and study was assessed by fitting interaction terms. Heterogeneity by each of invasiveness, family history, bilaterality, and hormone receptor status was assessed by subclassifying case patients and applying polytomous logistic regression. All statistical tests were two-sided. Results: We found strong evidence of association between rs13387042 and breast cancer in white women of European origin (per-allele OR = 1.12, 95% confidence interval [CI] = 1.09 to 1.15; Ptrend = 1.0 x 10–19). The odds ratio was lower than that previously reported (P = .02) and did not vary by age or ethnicity (all P .2). However, it was higher when the analysis was restricted to case patients who were selected for a strong family history (P = .02). An association was observed for both ER-positive (OR = 1.14, 95% CI = 1.10 to 1.17; P = 10–15) and ER-negative disease (OR = 1.10, 95% CI = 1.04 to 1.15; P = .0003) and both progesterone receptor (PR)–positive (OR = 1.15, 95% CI = 1.11 to 1.19; P = 5 x 10–14) and PR-negative disease (OR = 1.10, 95% CI = 1.06 to 1.15; P = .00002). Conclusion: The rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women. Roger L. Milne, Javier Benitez, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomaki, Carl Blomqvist, Jose Ignacio Arias, M. Pilar Zamora, Barbara Burwinkel, Claus R. Bartram, Alfons Meindl, Rita K. Schmutzler, Angela Cox, Ian Brock, Graeme Elliott, Malcolm W. R. Reed, Melissa C. Southey, Letitia Smith, Amanda B. Spurdle, John L. Hopper, Fergus J. Couch, Janet E. Olson, Xianshu Wang, Zachary Fredericksen, Peter Schurmann, Michael Bremer, Peter Hillemanns, Thilo Dork, Peter Devilee, Christie J. van Asperen, Rob A. E. M. Tollenaar, Caroline Seynaeve, Per Hall, Kamila Czene, Jianjun Liu, Yuqing Li, Shahana Ahmed, Alison M. Dunning, Melanie Maranian, Paul D. P. Pharoah, Georgia Chenevix-Trench, Jonathan Beesley, kConFab Investigators,, AOCS Group, Natalia V. Bogdanova, Natalia N. Antonenkova, Iosif V. Zalutsky, Hoda Anton-Culver, Argyrios Ziogas, Hiltrud Brauch, Christina Justenhoven, Yon-Dschun Ko, Susanne Haas, Peter A. Fasching, Reiner Strick, Arif B. Ekici, Matthias W. Beckmann, Graham G. Giles, Gianluca Severi, Laura Baglietto, Dallas R. English, Olivia Fletcher, Nichola Johnson, Isabel dos Santos Silva, Julian Peto, Clare Turnbull, Sarah Hines, Anthony Renwick, Nazneen Rahman, Borge G. Nordestgaard, Stig E. Bojesen, Henrik Flyger, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Montserrat Garcia-Closas, Stephen Chanock, Jolanta Lissowska, Louise A. Brinton, Jenny Chang-Claude, Shan Wang-Gohrke, Chen-Yang Shen, Hui-Chun Wang, Jyh-Cherng Yu, Sou-Tong Chen, Marina Bermisheva, Tatjana Nikolaeva, Elza Khusnutdinova, Manjeet K. Humphreys, Jonathan Morrison, Radka Platte, Douglas F. Easton, on behalf of the Breast Cancer Association Consortium
Published: 2009

44. Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Author: Martine Tranchant, Fergus J. Couch, Meeri Otsukka, Sabine Behrens, Jirong Long, Nadia Obi, Kamila Czene, John L. Hopper, Heather Thorne, Robert Pilarski, Anja Rudolph, Simon S. Cross, Volker Harth, Gabrielle Colleran, Hatef Darabi, Thomas Van Brussel, Eunjung Lee, Anne Lotz, E. Krol-Warmerdam, M. Pilar Zamora, Qin Wang, Andy C. H. Lee, Annie Fung, Kara Sargus, Melissa C. Southey, Katja Butterbach, Nuria Álvarez, Francois Bacot, Jeffrey G. Meyer, Ian W. Brock, Jessica Clague De Hart, Pierre Laurent-Puig, Irene L. Andrulis, Pei Chao, Arnaud Droit, Per Hall, Daniel C. Tessier, Paolo Radice, Frederic Robidoux, Don M. Conroy, Irja Erkkilä, Daniel Vincent, Antoinette Hollestelle, Christopher A. Hilker, Alicia Beeghly-Fadiel, Muhabbet Celik, Peggy Reynolds, Caroline Baynes, Sophia S. Wang, Katri Pylkäs, Kang In Nee, Robert Winqvist, Henrik Flyger, Annette Heemskerk, Sara Margolin, Hui Cai, Julie M. Cunningham, Prat Boonyawongviroj, Bernardo Bonanni, Anthony J. Swerdlow, Dan Connley, Huiyan Ma, Valerie Gaborieau, David O. Nelson, Keitaro Matsuo, Sylvie La Boissière, Pornthep Siriwanarungsan, Hidemi Ito, Ursula Eilber, Matthias W. Beckmann, Sylvia Rabstein, Natalia Bogdanova, Anna Jakubowska, Yves Raoul, Robert A.E.M. Tollenaar, Frans B. L. Hogervorst, Hannah L Park, Pierre Kerbrat, Ying Zheng, Paul D.P. Pharoah, Wanqing Wen, Judith Heinz, Annika Lindblom, Christa Stegmaier, Manjeet K. Bolla, Loris Bernard, Anna H. Wu, Alison M. Dunning, Hermann Brenner, A. Green, Thilo Dörk, Chia-Ni Hsiung, Dennis Deapen, Michael G. Schrauder, Gilian Peuteman, S.E. Higham, Sabapathy P. Balasubramanian, Irene Feroce, Christina Justenhoven, Angela Jones, William J. Blot, Nichola Johnson, Petra Seibold, D. Bowtell, Jiajun Shi, Wei Zheng, U Hamann, Pascal Guenel, P. Webb, Soo Hwang Teo, Daniela Zaffaroni, J. Blom, Rita K. Schmutzler, Douglas F. Easton, Yani Lu, Witold Zatonski, Phuah Sze Yee, Susan L. Neuhausen, Kenneth Muir, Sofia Khan, Daehee Kang, Silke Landrith, Helena Kemiläinen, Maggie Angelakos, Rich Pinder, Javier Benitez, Til Olchers, Senno Verhoef, Fred Schumacher, Martha J. Shrubsole, Teresa Selander, Teh Yew Ching, Christof Sohn, Patrick Arveux, Dorota M. Gertig, Saila Kauppila, Mervi Grip, Florentia Fostira, Jenny Chang-Claude, Michael Stagner, Kathleen Corthouts, Ellen Van Der Schoot, H Nevanlinna, Peter Bugert, Christian Baisch, Eija Myöhänen, Sonja Wolf, Hoda Anton-Culver, Nicola Miller, Cheng Har Yip, Neonila Szeszenia-Dabrowska, Nicholas K. Hayward, Dieter Flesch-Janys, Barbara Burwinkel, J. Molenaar, Eileen Williams, Marjanka K. Schmidt, Yon Ko, Anja Nieuwlaat, Chen-Yang Shen, Veli-Matti Kosma, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Artitaya Lophatananon, Mikael Hartman, Jonathan Beesley, Bernard Peissel, Paolo Peterlongo, Ji Yeob Choi, Craig Luccarini, Rosalind A. Eeles, Niall M. McInerney, Bernard Thienpont, Xiao-Ou Shu, Léa Héguy, Maya Ghoussaini, Sander Canisius, Wing-Yee Lo, Suleeporn Sangrajrang, Nur Aishah Taib, June Yashiki, Kirsimari Aaltonen, Louise A. Brinton, Elinor J. Sawyer, Alina Vrieling, Angela Cox, Frederik Marmé, Matthias Rübner, Graham G. Giles, Sonja Oeser, Hans Christiansen, Andrew Rowan, Ed Dicks, Andeas Schneeweiß, Catriona McLean, Antonis C. Antoniou, B. Pesch, Eveline Niedermayr, Volker Arndt, Janet E. Olson, Dominiek Smeets, Jingmei Li, Georgia Chenevix-Trench, Claire Mulot, Siranoush Manoukian, Hans Fischer, Ellen Crepin, Arto Mannermaa, Ali Amin Al Olama, Helen Cramp, Ans M.W. van den Ouweland, Olivia Fletcher, Sharon A. Windebank, Peter Hillemanns, Nayana Weerasooriya, James V. Lacey, Leslie Bernstein, Romuald Le Scodan, Giulietta Scuvera, P. Parsons, Thomas C. Putti, Elaine Ryder-Mills, Sara Benlloch, Beata Peplonska, Stig E. Bojesen, Kimberley Chua, Stefan Nickels, Nick Orr, Roger L. Milne, Tuomas Heikkinen, Christopher A. Haiman, Natalia Antonenkova, Volker Hermann, Maria Kabisch, Kenneth Offit, Julia A. Knight, Angela Maniscalco, Arja Jukkola-Vuorinen, Hartwig Ziegler, Chenjie Zeng, Jacques Simard, Pamela L. Horn-Ross, Daphne S.C. Lee, Xingyi Guo, Jan Lubinski, Michael J. Kerin, Loic Le Marchand, Sune F. Nielsen, Peter Devilee, A. De Fazio, Qiuyin Cai, Annie Turgeon, Yoon Sook-Yee, Silje Nord, Petra Bos, Hiltrud Brauch, Kyriaki Michailidou, Shivaani Mariapun, Kari Mononen, Alfons Meindl, Peter B. Kang, Siddhartha Kar, Alessandra Rossi, G. Chenevix-Trench, Diether Lambrechts, Karl von Smitten, Zsofia Kote-Jarai, Emiel J. Th. Rutgers, Chiu-Chen Tseng, Peter A. Fasching, Lesley McGuffog, Annegien Broekss, Johann H. Karstens, Montserrat Garcia-Closas, Thomas Brüning, David C. Whiteman, Judi Maskiell, Clinical Genetics, Cardiothoracic Surgery, Medical Oncology, and Obstetrics & Gynecology
Subjects: Genetic Markers, Linkage disequilibrium, Epidemiology, Locus (genetics), Genome-wide association study, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Article, Breast cancer, SDG 3 - Good Health and Well-being, Risk Factors, medicine, Humans, Genetic Predisposition to Disease, Gene, Genetics, Molecular epidemiology, Case-control study, Chromosome Mapping, medicine.disease, Logistic Models, Oncology, Genetic marker, Genetic Loci, Case-Control Studies, Female, Chromosomes, Human, Pair 4, Genome-Wide Association Study
Abstract: Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(11); 1680–91. ©2015 AACR.
Published: 2015

45. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

Author: Kate, Lawrenson, Edwin S, Iversen, Jonathan, Tyrer, Rachel Palmieri, Weber, Patrick, Concannon, Dennis J, Hazelett, Qiyuan, Li, Jeffrey R, Marks, Andrew, Berchuck, Janet M, Lee, Katja K H, Aben, Hoda, Anton-Culver, Natalia, Antonenkova, Elisa V, Bandera, Yukie, Bean, Matthias W, Beckmann, Maria, Bisogna, Line, Bjorge, Natalia, Bogdanova, Louise A, Brinton, Angela, Brooks-Wilson, Fiona, Bruinsma, Ralf, Butzow, Ian G, Campbell, Karen, Carty, Jenny, Chang-Claude, Georgia, Chenevix-Trench, Ann, Chen, Zhihua, Chen, Linda S, Cook, Daniel W, Cramer, Julie M, Cunningham, Cezary, Cybulski, Joanna, Plisiecka-Halasa, Joe, Dennis, Ed, Dicks, Jennifer A, Doherty, Thilo, Dörk, Andreas, du Bois, Diana, Eccles, Douglas T, Easton, Robert P, Edwards, Ursula, Eilber, Arif B, Ekici, Peter A, Fasching, Brooke L, Fridley, Yu-Tang, Gao, Aleksandra, Gentry-Maharaj, Graham G, Giles, Rosalind, Glasspool, Ellen L, Goode, Marc T, Goodman, Jacek, Gronwald, Philipp, Harter, Hanis Nazihah, Hasmad, Alexander, Hein, Florian, Heitz, Michelle A T, Hildebrandt, Peter, Hillemanns, Estrid, Hogdall, Claus, Hogdall, Satoyo, Hosono, Anna, Jakubowska, James, Paul, Allan, Jensen, Beth Y, Karlan, Susanne Kruger, Kjaer, Linda E, Kelemen, Melissa, Kellar, Joseph L, Kelley, Lambertus A, Kiemeney, Camilla, Krakstad, Diether, Lambrechts, Sandrina, Lambrechts, Nhu D, Le, Alice W, Lee, Rikki, Cannioto, Arto, Leminen, Jenny, Lester, Douglas A, Levine, Dong, Liang, Jolanta, Lissowska, Karen, Lu, Jan, Lubinski, Lene, Lundvall, Leon F A G, Massuger, Keitaro, Matsuo, Valerie, McGuire, John R, McLaughlin, Heli, Nevanlinna, Iain, McNeish, Usha, Menon, Francesmary, Modugno, Kirsten B, Moysich, Steven A, Narod, Lotte, Nedergaard, Roberta B, Ness, Mat Adenan, Noor Azmi, Kunle, Odunsi, Sara H, Olson, Irene, Orlow, Sandra, Orsulic, Celeste L, Pearce, Tanja, Pejovic, Liisa M, Pelttari, Jennifer, Permuth-Wey, Catherine M, Phelan, Malcolm C, Pike, Elizabeth M, Poole, Susan J, Ramus, Harvey A, Risch, Barry, Rosen, Mary Anne, Rossing, Joseph H, Rothstein, Anja, Rudolph, Ingo B, Runnebaum, Iwona K, Rzepecka, Helga B, Salvesen, Agnieszka, Budzilowska, Thomas A, Sellers, Xiao-Ou, Shu, Yurii B, Shvetsov, Nadeem, Siddiqui, Weiva, Sieh, Honglin, Song, Melissa C, Southey, Lara, Sucheston, Ingvild L, Tangen, Soo-Hwang, Teo, Kathryn L, Terry, Pamela J, Thompson, Agnieszka, Timorek, Shelley S, Tworoger, Els, Van Nieuwenhuysen, Ignace, Vergote, Robert A, Vierkant, Shan, Wang-Gohrke, Christine, Walsh, Nicolas, Wentzensen, Alice S, Whittemore, Kristine G, Wicklund, Lynne R, Wilkens, Yin-Ling, Woo, Xifeng, Wu, Anna H, Wu, Hannah, Yang, Wei, Zheng, Argyrios, Ziogas, Gerhard A, Coetzee, Matthew L, Freedman, Alvaro N A, Monteiro, Joanna, Moes-Sosnowska, Jolanta, Kupryjanczyk, Paul D, Pharoah, Simon A, Gayther, and Joellen M, Schildkraut
Subjects: Cancer Research, endocrine system diseases, Genome-wide association study, Carcinoma, Ovarian Epithelial, Risk Factors, Neoplasms, Ovarian Epithelial, 2.1 Biological and endogenous factors, Neoplasms, Glandular and Epithelial, Aetiology, skin and connective tissue diseases, Cancer, Genetics, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Glandular and Epithelial, General Medicine, Single Nucleotide, female genital diseases and pregnancy complications, Ovarian Cancer, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Biotechnology, Australian Ovarian Cancer Study Group, Quantitative Trait Loci, Oncology and Carcinogenesis, Locus (genetics), Single-nucleotide polymorphism, Original Manuscript, Biology, Polymorphism, Single Nucleotide, Rare Diseases, Clinical Research, Australian Cancer Study, SNP, Humans, Genetic Predisposition to Disease, Genetic Testing, Oncology & Carcinogenesis, 1000 Genomes Project, Polymorphism, CHEK2, Genetic association, Prevention, Carcinoma, Human Genome, Checkpoint Kinase 2, Genetic Loci, Case-Control Studies, Cancer research, Imputation (genetics), Genome-Wide Association Study
Abstract: Contains fulltext : 152042.pdf (Publisher’s version ) (Closed access) Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P
Published: 2015

46. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Author: Rosalind Glasspool, Lynne R. Wilkens, Camilla Krakstad, Diana Eccles, Liisa M. Pelttari, Thomas A. Sellers, Anja Rudolph, Estrid Høgdall, Yurii B. Shvetsov, Matthias W. Beckmann, Ignace Vergote, Angela Brooks-Wilson, Ingo B. Runnebaum, Joellen M. Schildkraut, Joe Dennis, Ingvild L. Tangen, Elizabeth M. Poole, Arif B. Ekici, Xiao-Ou Shu, Alice S. Whittemore, Valerie McGuire, Kunle Odunsi, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, Keitaro Matsuo, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Douglas T. Easton, Simon A. Gayther, Anna deFazio, Ian G. Campbell, Hanis Nazihah Hasmad, Shashi Lele, Maria Bisogna, Zhihua Chen, Usha Menon, Jenny Lester, Ursula Eilber, Iwona K. Rzepecka, Shan Wang-Gohrke, Steven A. Narod, Qiyuan Li, Dong Liang, Jonathan Tyrer, Kate Lawrenson, Hoda Anton-Culver, Alvaro N.A. Monteiro, Ed Dicks, Lene Lundvall, Sandra Orsulic, Brooke L. Fridley, Ellen L. Goode, Linda E. Kelemen, Edwin S. Iversen, Ya Yu Tsai, Mary Anne Rossing, Karen Carty, Thilo Dörk, Penelope M. Webb, Yukie Bean, Matthias Dürst, Soo Hwang Teo, Claus Høgdall, Robert P. Edwards, Alison M. Karst, Yu-Tang Gao, Harvey A. Risch, Patricia Harrington, Daniel W. Cramer, Ji-Heui Seo, Douglas A. Levine, Christine Walsh, Karen Lu, Elisa V. Bandera, Louise A. Brinton, Satoyo Hosono, Hannah P. Yang, Graham G. Giles, Robert A. Vierkant, Argyrios Ziogas, Honglin Song, Ian McNeish, Anne M. van Altena, Tanja Pejovic, Florian Heitz, Beth Y. Karlan, Kirsten B. Moysich, Philipp Harter, Joseph L. Kelley, Andrew Berchuck, Paul A. James, Peter Hillemanns, Susan J. Ramus, Jacek Grownwald, Celeste Leigh Pearce, Ronny Drapkin, Kristine G. Wicklund, Mat Adenan Noor Azmi, Lara Sucheston, Alexander Hein, Jolanta Kupryjanczyk, Ralf Bützow, Georgia Chenevix-Trench, Michelle A.T. Hildebrandt, Francesmary Modugno, John R. McLaughlin, Arto Leminen, Nicolas Wentzensen, Siddhartha Kar, Sara H. Olson, Susanne K. Kjaer, Barry P. Rosen, Andreas du Bois, Linda S. Cook, Jennifer A. Doherty, Joseph H. Rothstein, Aleksandra Gentry-Maharaj, Julie M. Cunningham, Leon F.A.G. Massuger, Irene Orlow, Rachel Palmieri Weber, Pamela J. Thompson, Tassja J. Spindler, Jenny Chang-Claude, Jennifer Permuth-Wey, Catherine M. Phelan, Yi-Bu Chen, Bu Tian Ji, Heli Nevanlinna, Roberta B. Ness, Shelley S. Tworoger, Allan Jensen, Anna H. Wu, Malcolm C. Pike, Fiona Bruinsma, Line Bjørge, Jolanta Lissowska, Natalia Antonenkova, Cezary Cybulski, Wei Zheng, Lotte Nedergaard, Els Van Nieuwenhuysen, Anne Chen, Janet M. Lee, David D.L. Bowtell, Helen Baker, Katja K.H. Aben, Xifeng Wu, Melissa Kellar, Weiva Sieh, Nhu D. Le, Marc T. Goodman, Matthew L. Freedman, Yin Ling Woo, Sandrina Lambrechts, Peter A. Fasching, Diether Lambrechts, Kathryn L. Terry, Ira Schwaab, Jan Lubinski, Natalia Bogdanova, Helga B. Salvesen, Alice W. Lee, Agnieszka Timorek, Nadeem Siddiqui, Department of Pathology, Medicum, Department of Obstetrics and Gynecology, Clinicum, and HUS Gynecology and Obstetrics
Subjects: EXPRESSION, Quantitative Trait Loci, General Physics and Astronomy, Locus (genetics), Genome-wide association study, Quantitative trait locus, Biology, Carcinoma, Ovarian Epithelial, VARIANTS, ANALYSES REVEAL, BREAST, General Biochemistry, Genetics and Molecular Biology, Article, Nuchal Cord, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, 3123 Gynaecology and paediatrics, Cell Line, Tumor, Genetic predisposition, SNP, Humans, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial, GENOME-WIDE ASSOCIATION, Genetic Association Studies, 030304 developmental biology, Genetic association, Genetics, Homeodomain Proteins, Ovarian Neoplasms, 0303 health sciences, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Multidisciplinary, LONG-RANGE INTERACTION, IDENTIFICATION, General Chemistry, RISK LOCI, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, FALLOPIAN-TUBE, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Expression quantitative trait loci, Female, 3111 Biomedicine, HOX GENES, Protein Binding
Abstract: Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10−5). For three cis-eQTL associations (P, Genome-wide association studies have identified regions which confer risk of high-grade serous epithelial ovarian cancer. Here the authors use expression quantitative train locus analysis to identify candidate genes and functionally characterise them, identifying a role for HOXD9 in ovarian cancer.
Published: 2015

47. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

Author: Ernest K, Amankwah, Hui-Yi, Lin, Jonathan P, Tyrer, Kate, Lawrenson, Joe, Dennis, Ganna, Chornokur, Katja K H, Aben, Hoda, Anton-Culver, Natalia, Antonenkova, Fiona, Bruinsma, Elisa V, Bandera, Yukie T, Bean, Matthias W, Beckmann, Maria, Bisogna, Line, Bjorge, Natalia, Bogdanova, Louise A, Brinton, Angela, Brooks-Wilson, Clareann H, Bunker, Ralf, Butzow, Ian G, Campbell, Karen, Carty, Zhihua, Chen, Y Ann, Chen, Jenny, Chang-Claude, Linda S, Cook, Daniel W, Cramer, Julie M, Cunningham, Cezary, Cybulski, Agnieszka, Dansonka-Mieszkowska, Andreas, du Bois, Evelyn, Despierre, Ed, Dicks, Jennifer A, Doherty, Thilo, Dörk, Matthias, Dürst, Douglas F, Easton, Diana M, Eccles, Robert P, Edwards, Arif B, Ekici, Peter A, Fasching, Brooke L, Fridley, Yu-Tang, Gao, Aleksandra, Gentry-Maharaj, Graham G, Giles, Rosalind, Glasspool, Marc T, Goodman, Jacek, Gronwald, Patricia, Harrington, Philipp, Harter, Hanis N, Hasmad, Alexander, Hein, Florian, Heitz, Michelle A T, Hildebrandt, Peter, Hillemanns, Claus K, Hogdall, Estrid, Hogdall, Satoyo, Hosono, Edwin S, Iversen, Anna, Jakubowska, Allan, Jensen, Bu-Tian, Ji, Beth Y, Karlan, Heather, Jim, Melissa, Kellar, Lambertus A, Kiemeney, Camilla, Krakstad, Susanne K, Kjaer, Jolanta, Kupryjanczyk, Diether, Lambrechts, Sandrina, Lambrechts, Nhu D, Le, Alice W, Lee, Shashi, Lele, Arto, Leminen, Jenny, Lester, Douglas A, Levine, Dong, Liang, Boon Kiong, Lim, Jolanta, Lissowska, Karen, Lu, Jan, Lubinski, Lene, Lundvall, Leon F A G, Massuger, Keitaro, Matsuo, Valerie, McGuire, John R, McLaughlin, Ian, McNeish, Usha, Menon, Roger L, Milne, Francesmary, Modugno, Kirsten B, Moysich, Roberta B, Ness, Heli, Nevanlinna, Ursula, Eilber, Kunle, Odunsi, Sara H, Olson, Irene, Orlow, Sandra, Orsulic, Rachel Palmieri, Weber, James, Paul, Celeste L, Pearce, Tanja, Pejovic, Liisa M, Pelttari, Jennifer, Permuth-Wey, Malcolm C, Pike, Elizabeth M, Poole, Harvey A, Risch, Barry, Rosen, Mary Anne, Rossing, Joseph H, Rothstein, Anja, Rudolph, Ingo B, Runnebaum, Iwona K, Rzepecka, Helga B, Salvesen, Eva, Schernhammer, Ira, Schwaab, Xiao-Ou, Shu, Yurii B, Shvetsov, Nadeem, Siddiqui, Weiva, Sieh, Honglin, Song, Melissa C, Southey, Beata, Spiewankiewicz, Lara, Sucheston-Campbell, Soo-Hwang, Teo, Kathryn L, Terry, Pamela J, Thompson, Lotte, Thomsen, Ingvild L, Tangen, Shelley S, Tworoger, Anne M, van Altena, Robert A, Vierkant, Ignace, Vergote, Christine S, Walsh, Shan, Wang-Gohrke, Nicolas, Wentzensen, Alice S, Whittemore, Kristine G, Wicklund, Lynne R, Wilkens, Anna H, Wu, Xifeng, Wu, Yin-Ling, Woo, Hannah, Yang, Wei, Zheng, Argyrios, Ziogas, Linda E, Kelemen, Andrew, Berchuck, Joellen M, Schildkraut, Susan J, Ramus, Ellen L, Goode, Alvaro N A, Monteiro, Simon A, Gayther, Steven A, Narod, Paul D P, Pharoah, Thomas A, Sellers, and Catherine M, Phelan
Subjects: Adult, Ovarian Neoplasms, Risk, Epithelial-Mesenchymal Transition, Genotype, Carcinoma, Ovarian Epithelial, Middle Aged, Polymorphism, Single Nucleotide, White People, Article, Odds Ratio, Humans, Female, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial, Aged, Genome-Wide Association Study
Abstract: Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value0.05 and a false discovery rate (FDR)0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.
Published: 2015

48. Shared genetics underlying epidemiological association between endometriosis and ovarian cancer

Author: C B Gilks, Anna H. Wu, Natalia Antonenkova, Weiva Sieh, Angela Brooks-Wilson, Liisa M. Pelttari, Ingo B. Runnebaum, Argyrios Ziogas, John R. McLaughlin, Arto Leminen, Jennifer A. Doherty, Aben Kkh., Jacek Gronwald, Diana Eccles, Kirsten B. Moysich, Jonathan Tyrer, Valerie McGuire, Julie M. Cunningham, Georgia Chenevix-Trench, Agnieszka Timorek, Penelope M. Webb, Estrid Høgdall, Shelley S. Tworoger, Allan Jensen, Stuart MacGregor, Line Bjørge, Matthias W. Beckmann, Joellen M. Schildkraut, Sara H. Olson, Adriaan Vanderstichele, Shan Wang-Gohrke, Jan Gawełko, Elizabeth M. Poole, Anja Rudolph, Francesmary Modugno, Marc T. Goodman, Usha Menon, Hoda Anton-Culver, Celeste Leigh Pearce, Kristine G. Wicklund, Hildebrandt Mat., Karen Lu, Elisa V. Bandera, Ignace Vergote, Peter A. Fasching, Susanne K. Kjaer, Honglin Song, Catherine M. Phelan, Pharoah Pdp., Simon A. Gayther, Fanny Dao, Maria Bisogna, Dong Liang, Massuger Lfag., Linda S. Cook, Steven A. Narod, Andrew Berchuck, Lukasz Szafron, Harvey A. Risch, Robert P. Edwards, Peter Hillemanns, Diether Lambrechts, Matthias Dürst, Stacey J. Winham, Rikki Cannioto, Alice S. Whittemore, Stacey A. Missmer, Jan Lubinski, Jolanta Kupryjanczyk, Susan J. Ramus, Jodie N. Painter, Nicolas Wentzensen, Brooke L. Fridley, Katharina Bischof, Agnieszka Dansonka-Mieszkowska, Mary Anne Rossing, Thilo Dörk, Natalia Bogdanova, Reidun K. Kopperud, Helga B. Salvesen, Nhu D. Le, Yi Lu, Britton Trabert, Terry K. Morgan, Stefanie Burghaus, Douglas A. Levine, Graham G. Giles, Kathryn L. Terry, Roberta B. Ness, Anna Jakubowska, Dale R. Nyholt, E Van Nieuwenhuysen, Gabriel Cuellar-Partida, Lambertus A. Kiemeney, Fiona Bruinsma, Ralf Bützow, Louise A. Brinton, Grant W. Montgomery, Alexander Hein, Xifeng Wu, Daniel W. Cramer, Joseph H. Rothstein, Andrew P. Morris, Joseph L. Kelley, Heli Nevanlinna, Jolanta Lissowska, Ellen L. Goode, Krina T. Zondervan, Ursula Eilber, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Lu, Yi, Cuellar-Partida, Gabriel, Painter, Jodie N, Nyholt, Dale R, MacGregor, Stuart, Lee, Sang Hong, Australian Ovarian Cancer Study, and International Endogene Consortium (IEC)
Subjects: endometriosis, Oncology, Risk, medicine.medical_specialty, endocrine system diseases, genetic association studies, Serous carcinoma, Endometriosis, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Medizinische Fakultät, Internal medicine, Genetics, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, ddc:610, Molecular Biology, Genetics (clinical), Genetic Association Studies, 030304 developmental biology, Genetic association, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, 0303 health sciences, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Association Studies Articles, General Medicine, ovarian neoplasms, medicine.disease, 3. Good health, Serous fluid, ovarian cancer, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Clear cell carcinoma, Female, Ovarian cancer, genetic predisposition
Abstract: Contains fulltext : 153959.pdf (Publisher’s version ) (Closed access) Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07-0.89 and 0.40, 95% CI = 0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.
Published: 2015

49. Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study

Author: Xianshu Wang, Susan L. Slager, Bernardo Bonanni, Katarzyna Durda, Sze Yee Phuah, M. Pilar Zamora, Dong Young Noh, Gillian S. Dite, Chiun-Sheng Huang, Lorna Gibson, Argyrios Ziogas, Artitaya Lophatananon, Pascal Guénel, Valeria Pensotti, Vernon S. Pankratz, Graham G. Giles, Anna H. Wu, Natalia Antonenkova, Daniel Vincent, Antoinette Hollestelle, Malcolm W.R. Reed, Hans Ulrich Ulmer, Vesa Kataja, Dieter Flesch-Janys, Hermann Brenner, Hui Miao, Nichola Johnson, Rita K. Schmutzler, Francois Bacot, Hans Wildiers, Thilo Dörk, Mark S. Goldberg, Julian Peto, Thomas Rüdiger, Cox A, Børge G. Nordestgaard, Patrick Neven, Vessela N. Kristensen, Barbara Burwinkel, David Van Den Berg, Craig Luccarini, Joe Dennis, Emilie Cordina, Dominiek Smeets, Natalia Bogdanova, Jaana M. Hartikainen, Stefan Nickels, Jean Wang, Kyriaki Michailidou, Henrik Flyger, Daniel C. Tessier, Paolo Radice, Stephen J. Chanock, Mark E. Sherman, Arif B. Ekici, Matthias W. Beckmann, William Blot, Daehee Kang, Christopher A. Haiman, Florence Menegaux, Gianluca Severi, Mervi Grip, Ben P. Haynes, Melissa C. Southey, Simon S. Cross, Montserrat Garcia-Closas, Mitch Dowsett, Jenny Chang-Claude, Drakoulis Yannoukakos, Celine M. Vachon, Isabel dos Santos Silva, Elinor J. Sawyer, Katri Pylkäs, Cheng Har Yip, Joerg Heil, Manjeet K. Bolla, Heiko Müller, Jyh Cherng Yu, Janet E. Olson, Wei Zheng, Carl Blomqvist, Yon Ko, Minouk J. Schoemaker, Christof Sohn, Ming-Feng Hou, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Diether Lambrechts, Mikael Hartman, Douglas F. Easton, Chen-Yang Shen, Andreas Schneeweiss, Javier Benitez, Amanda E. Toland, Anna Marie Mulligan, Jacques Simard, Suleeporn Sangrajrang, Robert Winqvist, Stig E. Bojesen, Nick Orr, Martine Dumont, Heli Nevanlinna, James McKay, Valerie Gaborieau, Keitaro Matsuo, Christina Clarke Dur, Aida Karina Dieffenbach, Jonathan Beesley, Grethe I. Grenaker Alnæs, Taru A. Muranen, Paolo Peterlongo, Marjanka K. Schmidt, Peter Devillee, Olivia Fletcher, Frederik Marmé, Anna Jakubowska, Paul D.P. Pharoah, Paul Brennan, Jolanta Lissowska, Nils Schoof, Ji Yeob Choi, Hoda Anton-Culver, Femke Atsma, Per Hall, Anja Rudolph, Ian W. Brock, Elizabeth Folkerd, Veli-Matti Kosma, Soo H. Teo, Arto Mannermaa, Chiu-Chen Tseng, Fergus J. Couch, Anne Lise Børresen-Dale, Anthony J. Swerdlow, Hiltrud Brauch, Jose Ignacio Arias Perez, Frank Dudbridge, Lisa B. Signorello, Madeleine M. A. Tilanus-Linthorst, Jonine D. Figueroa, Christina Justenhoven, Ute Hamann, Julia A. Knight, Peter A. Fasching, Alan Ashworth, Stefan P. Renner, Zachary S. Fredericksen, Wei-Yen Lim, Sue K. Park, Annegien Broeks, Georgia Chenevix-Trench, Jan Lubinski, Gord Glendon, Kristiina Aittomäki, Maartje J. Hooning, Jianjun Liu, Volker Arndt, Alfons Meindl, Leslie Bernstein, Laura Baglietto, Mitul Shah, Belinda K. Cornes, John L. Hopper, Penny Soucy, Katarzyna Jaworska-Bieniek, Alison M. Dunning, Claus R. Bartram, Roger L. Milne, Michael Jones, Kenneth Muir, Irene L. Andrulis, Arja Jukkola-Vuorinen, Annika Lindblom, Michael J. Kerin, Nicola Miller, Carmel Apicella, Asta Försti, Anthony Tang, Laura J. van't Veer, Rogier A. Oldenburg, Neurology, Medical Oncology, Clinical Genetics, Surgery, and Cardiothoracic Surgery
Subjects: Physiology, chemistry.chemical_compound, 610 Medical sciences Medicine, 0302 clinical medicine, Risk Factors, Medizinische Fakultät, Genotype, Cytochrome P-450 CYP3A, Age of Onset, Reproductive History, Medicine(all), 0303 health sciences, Age Factors, twins, Middle Aged, 3. Good health, steroid-hormones, 030220 oncology & carcinogenesis, loci, Menarche, Veterinary (all), Female, Research Article, Adult, medicine.medical_specialty, premenopausal women, Breast Neoplasms, Estrone, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, White People, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, estradiol, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Genetic Association Studies, Aged, 030304 developmental biology, Gynecology, business.industry, Case-control study, medicine.disease, Clinical research, Premenopause, chemistry, sex-hormone levels, Cancer and Oncology, genome-wide association, Age of onset, business, serum
Abstract: Introduction We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years. Methods We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics. Results We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (Ptrend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (Ptrend = 0.005) but not cases (Ptrend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (Phet = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (ORhet = 0.84, 95% CI 0.75, 0.94; ORhom = 0.81, 95% CI 0.51, 1.30; Ptrend = 0.002) but not for those who had their menarche age ≤11 years (ORhet = 1.06, 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; Ptrend = 0.29). Conclusions To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.
Published: 2014

50. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

Author: Francois Bacot, Julie M. Cunningham, Shelley S. Tworoger, Robert S. Brown, Allan Jensen, Anja Rudolph, Jonathan Tyrer, Edwin S. Iversen, Tanja Pejovic, Lynne R. Wilkens, Sebastian M. Armasu, Alice S. Whittemore, Florian Heitz, Beth Y. Karlan, Yin Ling Woo, Karen Lu, Heather S. L. Jim, Bohdan Górski, Wei Zheng, Harvey A. Risch, Hui-Yi Lin, Arif B. Ekici, Rosalind Glasspool, Kimberly R. Kalli, Diether Lambrechts, Nathan Lee, Toru Nakanishi, Diana Eccles, Gottfried E. Konecny, Ian G. Campbell, Heli Nevanlinna, Thomas A. Sellers, Jin Q. Cheng, Agnieszka Dansonka-Mieszkowska, Argyrios Ziogas, Matthias W. Beckmann, Michael J. Birrer, Melissa C. Southey, Liisa M. Pelttari, Jolanta Kupryjanczyk, Camilla Krakstad, Elizabeth M. Poole, Robert A. Vierkant, Xiao-Ou Shu, Nicolas Wentzensen, Fumitaka Kikkawa, Y. Ann Chen, Celeste Leigh Pearce, Howard C. Shen, Allison F. Vitonis, Ya-Yu Tsai, Gerhard A. Coetzee, Jolanta Lissowska, Sandrina Lambrechts, Dong Liang, Kathryn L. Terry, Hannah P. Yang, Graham G. Giles, Daniel C. Tessier, Ira Schwaab, Anna H. Wu, Hoda Anton-Culver, Gianluca Severi, Stephen J. Chanock, Douglas F. Easton, Weiva Sieh, Natalia Antonenkova, Anne M. van Altena, Keitaro Matsuo, Anna Jakubowska, Paul D.P. Pharoah, Peter Hillemanns, Qiuyin Cai, Susanne K. Kjaer, Katja K.H. Aben, Kirsten B. Moysich, Estrid Høgdall, Ellen L. Goode, Lambertus A. Kiemeney, David Fenstermacher, Xiaotao Qu, Jesus Gonzalez-Bosquet, Daniel O. Stram, Irene Orlow, Joellen M. Schildkraut, Antonis C. Antoniou, Rachel Palmieri Weber, Satoyo Hosono, Jie Lin, Roberta B. Ness, Shan Wang-Gohrke, Simon A. Gayther, James Paul, Jill S. Barnholtz-Sloan, Usha Menon, Johnathan M. Lancaster, Jennifer A. Doherty, Stefan Nickels, Paola Raska, Jan Lubinski, Boon Kiong Lim, Elisabeth Wik, Aleksandra Gentry-Maharaj, Kate Lawrenson, Georgia Chenevix-Trench, Maureen E. Hoatlin, Stanley B. Kaye, Lotte Nedergaard, Natalia Bogdanova, Zhihua Chen, Janet M. Lee, Laura Baglietto, Francesmary Modugno, Linda E. Kelemen, Elisa V. Bandera, Montserrat Garcia-Closas, Helga B. Salvesen, Brooke L. Fridley, Rod Karevan, Houtan Noushmehr, Thilo Dörk, Ralf Bützow, Nhu D. Le, Douglas A. Levine, Sara H. Olson, Mine S. Cicek, Louise A. Brinton, Soo-Hwang Teo, Ignace Vergote, Pamela J. Thompson, Catherine M. Phelan, Marc T. Goodman, Linda S. Cook, Matthias Dürst, Malcolm C. Pike, Boris Winterhoff, Mari K. Halle, Andreas du Bois, Daniel Vincent, Valerie McGuire, Rebecca Sutphen, Peter A. Fasching, Jenny Chang-Claude, Stefan P. Renner, Jennifer Permuth-Wey, Aneliya Velkova, John McLaughlin, Kunle Odunsi, Greg Bloom, Leon F.A.G. Massuger, Arto Leminen, Melissa C. Larson, Iwona K. Rzepecka, Philipp Harter, Beata Spiewankiewicz, Mary Anne Rossing, Jacek Gronwald, Yurii B. Shvetsov, Claus Høgdall, Martin Gore, Angela Brooks-Wilson, Evelyn Despierre, Fergus J. Couch, Vijayalakshmi Shridhar, Ingo B. Runnebaum, James M. Flanagan, Galina Lurie, Alvaro N.A. Monteiro, Per Hall, Andrew Berchuck, Robert Edwards, Yong-Bing Xiang, Honglin Song, Susan J. Ramus, Famida Zulkifli, Lorna Rodriguez-Rodriguez, Steven A. Narod, Daniel W. Cramer, and Cancer Research UK
Subjects: Genetics and Molecular Biology (all), endocrine system diseases, General Physics and Astronomy, Genome-wide association study, Australian Ovarian Cancer Study, Aetiology, screening and detection [ONCOL 5], Female, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Chromosomes, Human, Pair 17, Genetic Predisposition to Disease, Chemistry (all), Biochemistry, Genetics and Molecular Biology (all), Physics and Astronomy (all), Carcinoma, Ovarian Epithelial, SITE POLYMORPHISMS, Biochemistry, 0302 clinical medicine, Polymorphism (computer science), Neoplasms, Ovarian Epithelial, Consortium of Investigators of Modifiers of BRCA1/2, GENETIC-VARIANTS, 2.1 Biological and endogenous factors, Aetiology, Cancer, Genetics, Midical sciences: 700::Clinical medical sciences: 750::Gynaecology and obstetrics: 756 [VDP], RISK, 0303 health sciences, COMMON INVERSION, Multidisciplinary, Glandular and Epithelial, Single Nucleotide, Aetiology, screening and detection Immune Regulation [ONCOL 5], female genital diseases and pregnancy complications, 3. Good health, Ovarian Cancer, Multidisciplinary Sciences, GENÉTICA, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, FUNCTIONAL ANNOTATION, Human, Biotechnology, Biology, Medisinske fag: 700::Klinisk medisinske fag: 750::Gynekologi og obstetrikk: 756 [VDP], BINDING-SITES, General Biochemistry, Genetics and Molecular Biology, Article, Chromosomes, 03 medical and health sciences, Rare Diseases, Translational research [ONCOL 3], Australian Cancer Study, MD Multidisciplinary, medicine, Polymorphism, GENOME-WIDE ASSOCIATION, Genotyping, PARKINSON-DISEASE, MAPT REGION, 030304 developmental biology, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Science & Technology, Molecular epidemiology, Hereditary cancer and cancer-related syndromes [ONCOL 1], MULTIDISCIPLINARY SCIENCES, MICRORNA EXPRESSION, Pair 17, Carcinoma, Human Genome, General Chemistry, Odds ratio, medicine.disease, Human genome, Ovarian cancer
Abstract: Contains fulltext : 118576.pdf (Publisher’s version ) (Open Access) Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.
Published: 2013

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