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1. Saliva-derived DNA is suitable for the detection of clonal haematopoiesis of indeterminate potential

Author: Robert L. O’Reilly, Jared Burke, Philip Harraka, Paul Yeh, Kerryn Howlett, Kiarash Behrouzfar, Amanda Rewse, Helen Tsimiklis, Graham G. Giles, Kristen J. Bubb, Stephen J. Nicholls, Roger L. Milne, and Melissa C. Southey
Subjects: Clonal haematopoiesis, CHIP, Somatic mutations, Next generation sequencing, Saliva, Blood, Medicine, Science
Abstract: Abstract Clonal haematopoiesis of indeterminate potential (CHIP) has been associated with many adverse health outcomes. However, further research is required to understand the critical genes and pathways relevant to CHIP subtypes, evaluate how CHIP clones evolve with time, and further advance functional characterisation and therapeutic studies. Large epidemiological studies are well placed to address these questions but often collect saliva rather than blood from participants. Paired saliva- and blood-derived DNA samples from 94 study participants were sequenced using a targeted CHIP-gene panel. The ten genes most frequently identified to carry CHIP-associated variants were analysed. Fourteen unique variants associated with CHIP, ten in DNMT3A, two in TP53 and two in TET2, were identified with a variant allele fraction (VAF) between 0.02 and 0.2 and variant depth ≥ 5 reads. Eleven of these CHIP-associated variants were detected in both the blood- and saliva-derived DNA sample. Three variants were detected in blood with a VAF > 0.02 but fell below this threshold in the paired saliva sample (VAF 0.008—0.013). Saliva-derived DNA is suitable for detecting CHIP-associated variants. Saliva can offer a cost-effective biospecimen that could both advance CHIP research and facilitate clinical translation into settings such as risk prediction, precision prevention, and treatment monitoring.
Published: 2024
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2. Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing

Author: Melissa C. Southey, James G. Dowty, Moeen Riaz, Jason A. Steen, Anne-Laure Renault, Katherine Tucker, Judy Kirk, Paul James, Ingrid Winship, Nicholas Pachter, Nicola Poplawski, Scott Grist, Daniel J. Park, Bernard J. Pope, Khalid Mahmood, Fleur Hammet, Maryam Mahmoodi, Helen Tsimiklis, Derrick Theys, Amanda Rewse, Amanda Willis, April Morrow, Catherine Speechly, Rebecca Harris, Robert Sebra, Eric Schadt, Paul Lacaze, John J. McNeil, Graham G. Giles, Roger L. Milne, John L. Hopper, and Tú Nguyen-Dumont
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing are urgently required. Most prior research has been based on women selected for high-risk features and more data is needed to make inference about breast cancer risk for women unselected for family history, an important consideration of population screening. We tested 1464 women diagnosed with breast cancer and 862 age-matched controls participating in the Australian Breast Cancer Family Study (ABCFS), and 6549 healthy, older Australian women enroled in the ASPirin in Reducing Events in the Elderly (ASPREE) study for rare germline variants using a 24-gene-panel. Odds ratios (ORs) were estimated using unconditional logistic regression adjusted for age and other potential confounders. We identified pathogenic variants in 11.1% of the ABCFS cases, 3.7% of the ABCFS controls and 2.2% of the ASPREE (control) participants. The estimated breast cancer OR [95% confidence interval] was 5.3 [2.1–16.2] for BRCA1, 4.0 [1.9–9.1] for BRCA2, 3.4 [1.4–8.4] for ATM and 4.3 [1.0–17.0] for PALB2. Our findings provide a population-based perspective to gene-panel testing for breast cancer predisposition and opportunities to improve predictors for identifying women who carry pathogenic variants in breast cancer predisposition genes.
Published: 2021
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3. Is RNASEL:p.Glu265* a modifier of early-onset breast cancer risk for carriers of high-risk mutations?

Author: Tú Nguyen-Dumont, Zhi L. Teo, Fleur Hammet, Alexis Roberge, Maryam Mahmoodi, Helen Tsimiklis, Daniel J. Park, Bernard J. Pope, Andrew Lonie, Miroslav K. Kapuscinski, Khalid Mahmood, ABCFR, David E. Goldgar, Graham G. Giles, Ingrid Winship, John L. Hopper, and Melissa C. Southey
Subjects: RNASEL:P.Glu265*, Breast cancer, Modifier risk gene, Early-onset cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Breast cancer risk for BRCA1 and BRCA2 pathogenic mutation carriers is modified by risk factors that cluster in families, including genetic modifiers of risk. We considered genetic modifiers of risk for carriers of high-risk mutations in other breast cancer susceptibility genes. Methods In a family known to carry the high-risk mutation PALB2:c.3113G>A (p.Trp1038*), whole-exome sequencing was performed on germline DNA from four affected women, three of whom were mutation carriers. Results RNASEL:p.Glu265* was identified in one of the PALB2 carriers who had two primary invasive breast cancer diagnoses before 50 years. Gene-panel testing of BRCA1, BRCA2, PALB2 and RNASEL in the Australian Breast Cancer Family Registry identified five carriers of RNASEL:p.Glu265* in 591 early onset breast cancer cases. Three of the five women (60%) carrying RNASEL:p.Glu265* also carried a pathogenic mutation in a breast cancer susceptibility gene compared with 30 carriers of pathogenic mutations in the 586 non-carriers of RNASEL:p.Glu265* (5%) (p
Published: 2018
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4. FANCM and RECQL genetic variants and breast cancer susceptibility: relevance to South Poland and West Ukraine

Author: Tú Nguyen-Dumont, Aleksander Myszka, Pawel Karpinski, Maria M. Sasiadek, Hayane Akopyan, Fleur Hammet, Helen Tsimiklis, Daniel J. Park, Bernard J. Pope, Ryszard Slezak, Nataliya Kitsera, Aleksandra Siekierzynska, and Melissa C. Southey
Subjects: FANCM, RECQL, Breast cancer predisposition, Familial breast cancer, Gene panel testing, Internal medicine, RC31-1245, Genetics, QH426-470
Abstract: Abstract Background FANCM and RECQL have recently been reported as breast cancer susceptibility genes and it has been suggested that they should be included on gene panel tests for breast cancer predisposition. However, the clinical value of testing for mutations in RECQL and FANCM remains to be determined. In this study, we have characterised the spectrum of FANCM and RECQL mutations in women affected with breast or ovarian cancer from South-West Poland and West Ukraine. Methods We applied Hi-Plex, an amplicon-based enrichment method for targeted massively parallel sequencing, to screen the coding exons and proximal intron-exon junctions of FANCM and RECQL in germline DNA from unrelated women affected with breast cancer (n = 338) and ovarian cancer (n = 89) from Poland (n = 304) and Ukraine (n = 123). These women were at high-risk of carrying a genetic predisposition to breast and/or ovarian cancer due to a family history and/or early-onset disease. Results Among 427 women screened, we identified one carrier of the FANCM:c.1972C > T nonsense mutation (0.23%), and two carriers of the frameshift insertion FANCM:c.1491dup (0.47%). None of the variants we observed in RECQL were predicted to be loss-of-function mutations by standard variant effect prediction tools. Conclusions Our study of the Polish and Ukrainian populations has identified a carrier frequency of truncating mutations in FANCM consistent with previous reports. Although initial reports suggesting that mutations in RECQL could be associated with increased breast cancer risk included women from Poland and identified the RECQL:c.1667_1667 + 3delAGTA mutation in 0.23–0.35% of breast cancer cases, we did not observe any carriers in our study cohort. Continued screening, both in research and diagnostic settings, will enable the accumulation of data that is needed to establish the clinical utility of including RECQL and FANCM on gene panel tests.
Published: 2018
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5. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Author: Fergus J. Couch, Karoline B. Kuchenbaecker, Kyriaki Michailidou, Gustavo A. Mendoza-Fandino, Silje Nord, Janna Lilyquist, Curtis Olswold, Emily Hallberg, Simona Agata, Habibul Ahsan, Kristiina Aittomäki, Christine Ambrosone, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Banu K. Arun, Brita Arver, Monica Barile, Rosa B. Barkardottir, Daniel Barrowdale, Lars Beckmann, Matthias W. Beckmann, Javier Benitez, Stephanie V. Blank, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldes, Maria A. Caligo, Federico Canzian, Jane Carpenter, Jenny Chang-Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen B. M. Claes, Angela Cox, Simon S. Cross, Julie M. Cunningham, Kamila Czene, Mary B. Daly, Francesca Damiola, Hatef Darabi, Miguel de la Hoya, Peter Devilee, Orland Diez, Yuan C. Ding, Riccardo Dolcetti, Susan M. Domchek, Cecilia M. Dorfling, Isabel dos-Santos-Silva, Martine Dumont, Alison M. Dunning, Diana M. Eccles, Hans Ehrencrona, Arif B. Ekici, Heather Eliassen, Steve Ellis, Peter A. Fasching, Jonine Figueroa, Dieter Flesch-Janys, Asta Försti, Florentia Fostira, William D. Foulkes, Tara Friebel, Eitan Friedman, Debra Frost, Marike Gabrielson, Marilie D. Gammon, Patricia A. Ganz, Susan M. Gapstur, Judy Garber, Mia M. Gaudet, Simon A. Gayther, Anne-Marie Gerdes, Maya Ghoussaini, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Marc Gunter, Lothar Haeberle, Christopher A. Haiman, Ute Hamann, Thomas V. O. Hansen, Steven Hart, Sue Healey, Tuomas Heikkinen, Brian E. Henderson, Josef Herzog, Frans B. L. Hogervorst, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Keith Humphreys, David J. Hunter, Tomasz Huzarski, Evgeny N. Imyanitov, Claudine Isaacs, Anna Jakubowska, Paul James, Ramunas Janavicius, Uffe Birk Jensen, Esther M. John, Michael Jones, Maria Kabisch, Siddhartha Kar, Beth Y. Karlan, Sofia Khan, Kay-Tee Khaw, Muhammad G. Kibriya, Julia A. Knight, Yon-Dschun Ko, Irene Konstantopoulou, Veli-Matti Kosma, Vessela Kristensen, Ava Kwong, Yael Laitman, Diether Lambrechts, Conxi Lazaro, Eunjung Lee, Loic Le Marchand, Jenny Lester, Annika Lindblom, Noralane Lindor, Sara Lindstrom, Jianjun Liu, Jirong Long, Jan Lubinski, Phuong L. Mai, Enes Makalic, Kathleen E. Malone, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, Frederik Marme, John W. M. Martens, Lesley McGuffog, Alfons Meindl, Austin Miller, Roger L. Milne, Penelope Miron, Marco Montagna, Sylvie Mazoyer, Anna M. Mulligan, Taru A. Muranen, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Janet E. Olson, Ana Osorio, Sue K. Park, Petra H. Peeters, Bernard Peissel, Paolo Peterlongo, Julian Peto, Catherine M. Phelan, Robert Pilarski, Bruce Poppe, Katri Pylkäs, Paolo Radice, Nazneen Rahman, Johanna Rantala, Christine Rappaport, Gad Rennert, Andrea Richardson, Mark Robson, Isabelle Romieu, Anja Rudolph, Emiel J. Rutgers, Maria-Jose Sanchez, Regina M. Santella, Elinor J. Sawyer, Daniel F. Schmidt, Marjanka K. Schmidt, Rita K. Schmutzler, Fredrick Schumacher, Rodney Scott, Leigha Senter, Priyanka Sharma, Jacques Simard, Christian F. Singer, Olga M. Sinilnikova, Penny Soucy, Melissa Southey, Doris Steinemann, Marie Stenmark-Askmalm, Dominique Stoppa-Lyonnet, Anthony Swerdlow, Csilla I. Szabo, Rulla Tamimi, William Tapper, Manuel R. Teixeira, Soo-Hwang Teo, Mary B. Terry, Mads Thomassen, Deborah Thompson, Laima Tihomirova, Amanda E. Toland, Robert A. E. M. Tollenaar, Ian Tomlinson, Thérèse Truong, Helen Tsimiklis, Alex Teulé, Rosario Tumino, Nadine Tung, Clare Turnbull, Giski Ursin, Carolien H. M. van Deurzen, Elizabeth J. van Rensburg, Raymonda Varon-Mateeva, Zhaoming Wang, Shan Wang-Gohrke, Elisabete Weiderpass, Jeffrey N. Weitzel, Alice Whittemore, Hans Wildiers, Robert Winqvist, Xiaohong R. Yang, Drakoulis Yannoukakos, Song Yao, M Pilar Zamora, Wei Zheng, Per Hall, Peter Kraft, Celine Vachon, Susan Slager, Georgia Chenevix-Trench, Paul D. P. Pharoah, Alvaro A. N. Monteiro, Montserrat García-Closas, Douglas F. Easton, and Antonis C. Antoniou
Subjects: Science
Abstract: Oestrogen negative breast cancer is associated with a poor prognosis. In this study, the authors perform a meta-analysis of 11 breast cancer genome-wide association studies and identify four new loci associated with oestrogen negative breast cancer risk. These findings may aid in stratifying patients in the clinic.
Published: 2016
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6. MicroRNA related polymorphisms and breast cancer risk.

Author: Sofia Khan, Dario Greco, Kyriaki Michailidou, Roger L Milne, Taru A Muranen, Tuomas Heikkinen, Kirsimari Aaltonen, Joe Dennis, Manjeet K Bolla, Jianjun Liu, Per Hall, Astrid Irwanto, Keith Humphreys, Jingmei Li, Kamila Czene, Jenny Chang-Claude, Rebecca Hein, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Olivia Fletcher, Julian Peto, Isabel dos Santos Silva, Nichola Johnson, Lorna Gibson, Zoe Aitken, John L Hopper, Helen Tsimiklis, Minh Bui, Enes Makalic, Daniel F Schmidt, Melissa C Southey, Carmel Apicella, Jennifer Stone, Quinten Waisfisz, Hanne Meijers-Heijboer, Muriel A Adank, Rob B van der Luijt, Alfons Meindl, Rita K Schmutzler, Bertram Müller-Myhsok, Peter Lichtner, Clare Turnbull, Nazneen Rahman, Stephen J Chanock, David J Hunter, Angela Cox, Simon S Cross, Malcolm W R Reed, Marjanka K Schmidt, Annegien Broeks, Laura J Van't Veer, Frans B Hogervorst, Peter A Fasching, Michael G Schrauder, Arif B Ekici, Matthias W Beckmann, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Javier Benitez, Pilar M Zamora, Jose I A Perez, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Paul D P Pharoah, Alison M Dunning, Mitul Shah, Robert Luben, Judith Brown, Fergus J Couch, Xianshu Wang, Celine Vachon, Janet E Olson, Diether Lambrechts, Matthieu Moisse, Robert Paridaens, Marie-Rose Christiaens, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Claire Mulot, Frederick Marme, Barbara Burwinkel, Andreas Schneeweiss, Christof Sohn, Elinor J Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Irene L Andrulis, Julia A Knight, Sandrine Tchatchou, Anna Marie Mulligan, Thilo Dörk, Natalia V Bogdanova, Natalia N Antonenkova, Hoda Anton-Culver, Hatef Darabi, Mikael Eriksson, Montserrat Garcia-Closas, Jonine Figueroa, Jolanta Lissowska, Louise Brinton, Peter Devilee, Robert A E M Tollenaar, Caroline Seynaeve, Christi J van Asperen, Vessela N Kristensen, kConFab Investigators, Australian Ovarian Cancer Study Group, Susan Slager, Amanda E Toland, Christine B Ambrosone, Drakoulis Yannoukakos, Annika Lindblom, Sara Margolin, Paolo Radice, Paolo Peterlongo, Monica Barile, Paolo Mariani, Maartje J Hooning, John W M Martens, J Margriet Collée, Agnes Jager, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Graham G Giles, Catriona McLean, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, GENICA Network, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Anthony Swerdlow, Alan Ashworth, Nick Orr, Michael Jones, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Arto Mannermaa, Ute Hamann, Georgia Chenevix-Trench, Carl Blomqvist, Kristiina Aittomäki, Douglas F Easton, and Heli Nevanlinna
Subjects: Medicine, Science
Abstract: Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
Published: 2014
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7. Supplementary Table 3 from Rare Mutations in RINT1 Predispose Carriers to Breast and Lynch Syndrome–Spectrum Cancers

Author: David E. Goldgar, Melissa C. Southey, Sean V. Tavtigian, Fabienne Lesueur, Bing-Jian Feng, John L. Hopper, Graham G. Giles, Peter Devilee, Henry T. Lynch, Carrie Snyder, Saundra S. Buys, Mary Daly, Mary B. Terry, Irene L. Andrulis, Esther M. John, Igor V. Makunin, Jun Li, Jonathan Ellis, Chad D. Huff, Hao Hu, Russell Bell, Terrell C. Roane, Bernard J. Pope, Andrew Lonie, Catherine Voegele, Erin L. Young, Louise B. Thingholm, Zhi L. Teo, Helen Tsimiklis, Fabrice Odefrey, Fleur Hammet, Nivonirina Robinot, Tu Nguyen-Dumont, Florence Le Calvez-Kelm, Kayoko Tao, and Daniel J. Park
Abstract: PDF file 65K, Primers used in assessment of RINT1 transcripts
Published: 2023
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8. Supplementary Figure 1 from Rare Mutations in RINT1 Predispose Carriers to Breast and Lynch Syndrome–Spectrum Cancers

Author: David E. Goldgar, Melissa C. Southey, Sean V. Tavtigian, Fabienne Lesueur, Bing-Jian Feng, John L. Hopper, Graham G. Giles, Peter Devilee, Henry T. Lynch, Carrie Snyder, Saundra S. Buys, Mary Daly, Mary B. Terry, Irene L. Andrulis, Esther M. John, Igor V. Makunin, Jun Li, Jonathan Ellis, Chad D. Huff, Hao Hu, Russell Bell, Terrell C. Roane, Bernard J. Pope, Andrew Lonie, Catherine Voegele, Erin L. Young, Louise B. Thingholm, Zhi L. Teo, Helen Tsimiklis, Fabrice Odefrey, Fleur Hammet, Nivonirina Robinot, Tu Nguyen-Dumont, Florence Le Calvez-Kelm, Kayoko Tao, and Daniel J. Park
Abstract: PDF file 199K, RINT1 c.1334-5delA, c.1334-1_1335delGTT minigene assay
Published: 2023
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9. Supplementary Table 1 from Rare Mutations in RINT1 Predispose Carriers to Breast and Lynch Syndrome–Spectrum Cancers

Author: David E. Goldgar, Melissa C. Southey, Sean V. Tavtigian, Fabienne Lesueur, Bing-Jian Feng, John L. Hopper, Graham G. Giles, Peter Devilee, Henry T. Lynch, Carrie Snyder, Saundra S. Buys, Mary Daly, Mary B. Terry, Irene L. Andrulis, Esther M. John, Igor V. Makunin, Jun Li, Jonathan Ellis, Chad D. Huff, Hao Hu, Russell Bell, Terrell C. Roane, Bernard J. Pope, Andrew Lonie, Catherine Voegele, Erin L. Young, Louise B. Thingholm, Zhi L. Teo, Helen Tsimiklis, Fabrice Odefrey, Fleur Hammet, Nivonirina Robinot, Tu Nguyen-Dumont, Florence Le Calvez-Kelm, Kayoko Tao, and Daniel J. Park
Abstract: PDF file 69K, Distribution of cases and controls included in the analysis, by study center and ethnic group
Published: 2023
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10. Mismatch repair gene pathogenic germline variants in a population-based cohort of breast cancer

Author: Derrick Theys, Melissa C. Southey, Maryam Mahmoodi, Fleur Hammet, Tu Nguyen-Dumont, Graham G. Giles, Daniel J. Park, Helen Tsimiklis, John L. Hopper, Bernard J. Pope, Mark Clendenning, Jason A. Steen, and Ingrid Winship
Subjects: Male, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Cancer Research, Victoria, Population, Breast Neoplasms, 030105 genetics & heredity, Biology, DNA Mismatch Repair, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Genetics, medicine, PMS2, Humans, Genetic Predisposition to Disease, Registries, education, Germ-Line Mutation, Genetics (clinical), Mismatch Repair Endonuclease PMS2, education.field_of_study, Cancer prevention, Gene Expression Profiling, Cancer, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, Lynch syndrome, Pedigree, DNA-Binding Proteins, MSH6, MutS Homolog 2 Protein, Oncology, MSH2, Case-Control Studies, 030220 oncology & carcinogenesis, Female, New South Wales, MutL Protein Homolog 1
Abstract: The advent of gene panel testing is challenging the previous practice of using clinically defined cancer family syndromes to inform single-gene genetic screening. Individual and family cancer histories that would have previously indicated testing of a single gene or a small number of related genes are now, increasingly, leading to screening across gene panels that contain larger numbers of genes. We have applied a gene panel test that included four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) to an Australian population-based case-control-family study of breast cancer. Altogether, eight pathogenic variants in MMR genes were identified: six in 1421 case-families (0.4%, 4 MSH6 and 2 PMS2) and two in 833 control-families (0.2%, one each of MLH1 and MSH2). This testing highlights the current and future challenges for clinical genetics in the context of anticipated gene panel-based population-based screening that includes the MMR genes. This testing is likely to provide additional opportunities for cancer prevention via cascade testing for Lynch syndrome and precision medicine for breast cancer treatment.
Published: 2020
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11. VTRNA2-1: Genetic Variation, Heritable Methylation and Disease Association

Author: Melissa C. Southey, Fleur Hammet, Timothy McKay, Chenglong Yu, Maryam Mahmoodi, Jihoon E. Joo, Roger L. Milne, Jason A. Steen, John L. Hopper, Tu Nguyen-Dumont, Helen Tsimiklis, Derrick Theys, kConFab, Graham G. Giles, James G. Dowty, Ee Ming Wong, and Pierre Antoine Dugué
Subjects: VTRNA2-1, methylation quantitative trait loci, Genome-wide association study, Quantitative trait locus, Article, Catalysis, lcsh:Chemistry, Inorganic Chemistry, nc886, breast cancer, Genetic variation, SNP, Physical and Theoretical Chemistry, lcsh:QH301-705.5, Molecular Biology, Spectroscopy, Genetics, rs2346018, Organic Chemistry, General Medicine, Methylation, Heritability, prostate cancer, MIR886, Computer Science Applications, SNP-based heritability, lcsh:Biology (General), lcsh:QD1-999, CpG site, DNA methylation
Abstract: VTRNA2-1 is a metastable epiallele with accumulating evidence that methylation at this region is heritable, modifiable and associated with disease including risk and progression of cancer. This study investigated the influence of genetic variation and other factors such as age and adult lifestyle on blood DNA methylation in this region. We first sequenced the VTRNA2-1 gene region in multiple-case breast cancer families in which VTRNA2-1 methylation was identified as heritable and associated with breast cancer risk. Methylation quantitative trait loci (mQTL) were investigated using a prospective cohort study (4500 participants with genotyping and methylation data). The cis-mQTL analysis (334 variants ± 50 kb of the most heritable CpG site) identified 43 variants associated with VTRNA2-1 methylation (p &lt, 1.5 × 10−4), however, these explained little of the methylation variation (R2 &lt, 0.5% for each of these variants). No genetic variants elsewhere in the genome were found to strongly influence VTRNA2-1 methylation. SNP-based heritability estimates were consistent with the mQTL findings (h2 = 0, 95%CI: −0.14 to 0.14). We found no evidence that age, sex, country of birth, smoking, body mass index, alcohol consumption or diet influenced blood DNA methylation at VTRNA2-1. Genetic factors and adult lifestyle play a minimal role in explaining methylation variability at the heritable VTRNA2-1 cluster.
Published: 2021
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12. Population-Based Estimates of the Age-Specific Cumulative Risk of Breast Cancer for Pathogenic Variants in CHEK2: Findings from the Australian Breast Cancer Family Registry

Author: Maryam Mahmoodi, Roger L. Milne, Derrick Theys, Tu Nguyen-Dumont, Fleur Hammet, Melissa C. Southey, Graham G. Giles, James G. Dowty, Amanda Rewse, John L. Hopper, Helen Tsimiklis, Ingrid Winship, Anne-Laure Renault, and Jason A. Steen
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Population, CHEK2, Population based, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, breast cancer, Internal medicine, medicine, genetic risk factors, penetrance, education, skin and connective tissue diseases, education.field_of_study, business.industry, age-specific cumulative risk, Hazard ratio, Cancer, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Penetrance, Age specific, Cumulative risk, Increased risk, Clinical research, 030104 developmental biology, predisposition, 030220 oncology & carcinogenesis, business
Abstract: 551 Background: Case-control studies of breast cancer have consistently shown that pathogenic variants in CHEK2 are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein truncating variant CHEK2c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all CHEK2 pathogenic (including likely pathogenic) variants combined. Methods: We conducted a genetic screen of CHEK2 in an Australian population-based case-control-family study of breast cancer. This study is focused on disease at an early age and participants were unselected for family history. The age-specific cumulative risk (penetrance) of breast cancer was estimated using segregation analysis. Results: The estimated hazard ratio for carriers of pathogenic CHEK2 variants (combined) was 4.9 (95% CI 2.5-9.5; p < 0.0001) relative to non-carriers. The HR for carriers of the CHEK2 c.1100delC variant was estimated to be 3.5 (95% CI 1.02-11.6) and the HR for carriers of all other CHEK2 variants combined was estimated to be 5.7 (95% CI 2.5-12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11-30%) and 33% (95% CI 21-48%) to age 60 and 80 years, respectively. Conclusions: These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2.
Published: 2021

13. Population-Based Estimates of the Age-Specific Cumulative Risk of Breast Cancer for Pathogenic Variants in

Author: Tú, Nguyen-Dumont, James G, Dowty, Jason A, Steen, Anne-Laure, Renault, Fleur, Hammet, Maryam, Mahmoodi, Derrick, Theys, Amanda, Rewse, Helen, Tsimiklis, Ingrid M, Winship, Graham G, Giles, Roger L, Milne, John L, Hopper, and Melissa C, Southey
Subjects: breast cancer, predisposition, age-specific cumulative risk, genetic risk factors, penetrance, skin and connective tissue diseases, Article, CHEK2
Abstract: Simple Summary It is well established that women who carry pathogenic CHEK2 variants have about a 3-fold increased risk of developing breast cancer. CHEK2 is now commonly included in genetic tests for breast cancer predisposition and increasingly used to inform the clinical management of women who are identified to carry pathogenic variants. Important information for counselling these women includes knowing how breast cancer risk, due to having a pathogenic variant in CHEK2, changes over a woman’s lifetime. This information is currently not well established. By conducting a population-based case-control-family study of pathogenic CHEK2 variants we aimed to provide this information and estimated the penetrance (age-specific cumulative risk) of breast cancer to be 18% (95% CI 11–30%) to age 60 years and 33% (95% CI 21–48%) to age 80 years. These findings provide new and important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2. Abstract Case-control studies of breast cancer have consistently shown that pathogenic variants in CHEK2 are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein-truncating variant CHEK2 c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all CHEK2 pathogenic (including likely pathogenic) variants combined. We conducted a population-based case-control-family study of pathogenic CHEK2 variants (26 families, 1071 relatives) and estimated the age-specific cumulative risk of breast cancer using segregation analysis. The estimated hazard ratio for carriers of pathogenic CHEK2 variants (combined) was 4.9 (95% CI 2.5–9.5) relative to non-carriers. The HR for carriers of the CHEK2 c.1100delC variant was estimated to be 3.5 (95% CI 1.02–11.6) and the HR for carriers of all other CHEK2 variants combined was estimated to be 5.7 (95% CI 2.5–12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11–30%) and 33% (95% CI 21–48%) to age 60 and 80 years, respectively. These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2.
Published: 2021

14. Human milk oligosaccharide profiles and allergic disease up to 18 years

Author: Shyamali C. Dharmage, Aaron E. Darling, Elasma Milanzi, Michael J. Abramson, Bianca Robertson, Gayan Bowatte, Cecilie Svanes, Lars Bode, Helen Tsimiklis, Christine Axelrad, Matthias Wjst, Caroline J Lodge, and Adrian J. Lowe
Subjects: 0301 basic medicine, Male, Risk, medicine.medical_specialty, Allergy, Adolescent, Immunology, Eczema, Oligosaccharides, Breast milk, Childhood, Human Milk Oligosaccharides, Latent Class Analysis, Atopy, 03 medical and health sciences, 0302 clinical medicine, Wheeze, Internal medicine, Immunology and Allergy, Medicine, Humans, Lactation, 030212 general & internal medicine, Child, health care economics and organizations, Asthma, Respiratory Sounds, Milk, Human, business.industry, Colostrum, Australia, Infant, Newborn, Infant, Odds ratio, medicine.disease, 030104 developmental biology, 1107 Immunology, Child, Preschool, Female, medicine.symptom, business, Food Hypersensitivity, Cohort study, Follow-Up Studies
Abstract: Background Human milk oligosaccharides (HMO) are a diverse range of sugars secreted in breast milk that have direct and indirect effects on immunity. The profiles of HMOs produced differ between mothers. Objective We sought to determine the relationship between maternal HMO profiles and offspring allergic diseases up to age 18 years. Methods Colostrum and early lactation milk samples were collected from 285 mothers enrolled in a high-allergy-risk birth cohort, the Melbourne Atopy Cohort Study. Nineteen HMOs were measured. Profiles/patterns of maternal HMOs were determined using LCA. Details of allergic disease outcomes including sensitization, wheeze, asthma, and eczema were collected at multiple follow-ups up to age 18 years. Adjusted logistic regression analyses and generalized estimating equations were used to determine the relationship between HMO profiles and allergy. Results The levels of several HMOs were highly correlated with each other. LCA determined 7 distinct maternal milk profiles with memberships of 10% and 20%. Compared with offspring exposed to the neutral Lewis HMO profile, exposure to acidic Lewis HMOs was associated with a higher risk of allergic disease and asthma over childhood (odds ratio asthma at 18 years, 5.82; 95% CI, 1.59-21.23), whereas exposure to the acidic-predominant profile was associated with a reduced risk of food sensitization (OR at 12 years, 0.08; 95% CI, 0.01-0.67). Conclusions In this high-allergy-risk birth cohort, some profiles of HMOs were associated with increased and some with decreased allergic disease risks over childhood. Further studies are needed to confirm these findings and realize the potential for intervention.
Published: 2021

15. Rare germline pathogenic variants identified by multigene panel testing and the risk of aggressive prostate cancer

Author: Pierre Antoine Dugué, Moeen Riaz, Graham G. Giles, James G. Dowty, Helen Tsimiklis, Melissa C. Southey, Damien M Bolton, Eric E. Schadt, Roger L. Milne, Maryam Mahmoodi, Fleur Hammet, Gianluca Severi, Tu Nguyen-Dumont, Anne-Laure Renault, Derrick Theys, Robert Sebra, John J McNeil, Robert J. MacInnis, Jason A. Steen, Paul Lacaze, Monash University [Melbourne], University of Melbourne, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), Mode de vie, génétique et santé : études intégratives et transgénérationnelles (U1018 (Équipe 9)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, National Health and Medical Research Council, NHMRC Monash University, MU APP1074383, Funding: This work was supported by a National Health and Medical Research Council (NMHRC, Australia) Program grant (APP1074383) and Monash University. TN-D is a National Breast Cancer Foundation (Australia) Career Development Fellow (ECF-17-001). M.C.S. is a NMHRC Senior Research Fellow (APP1155163)., and HAL UVSQ, Équipe
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Predisposition, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Logistic regression, urologic and male genital diseases, lcsh:RC254-282, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Article, Germline, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Gene panel testing, Gene, Likely pathogenic, business.industry, Cancer, Odds ratio, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Confidence interval, 3. Good health, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, Genetic risk factors, Aggressive prostate cancer, business
Abstract: While gene panel sequencing is becoming widely used for cancer risk prediction, its clinical utility with respect to predicting aggressive prostate cancer (PrCa) is limited by our current understanding of the genetic risk factors associated with predisposition to this potentially lethal disease phenotype. This study included 837 men diagnosed with aggressive PrCa and 7261 controls (unaffected men and men who did not meet criteria for aggressive PrCa). Rare germline pathogenic variants (including likely pathogenic variants) were identified by targeted sequencing of 26 known or putative cancer predisposition genes. We found that 85 (10%) men with aggressive PrCa and 265 (4%) controls carried a pathogenic variant (p &lt, 0.0001). Aggressive PrCa odds ratios (ORs) were estimated using unconditional logistic regression. Increased risk of aggressive PrCa (OR (95% confidence interval)) was identified for pathogenic variants in BRCA2 (5.8 (2.7–12.4)), BRCA1 (5.5 (1.8–16.6)), and ATM (3.8 (1.6–9.1)). Our study provides further evidence that rare germline pathogenic variants in these genes are associated with increased risk of this aggressive, clinically relevant subset of PrCa. These rare genetic variants could be incorporated into risk prediction models to improve their precision to identify men at highest risk of aggressive prostate cancer and be used to identify men with newly diagnosed prostate cancer who require urgent treatment.
Published: 2021
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16. Genetic testing in Poland and Ukraine: should comprehensive germline testing of

Author: Tu, Nguyen-Dumont, Pawel, Karpinski, Maria M, Sasiadek, Hayane, Akopyan, Jason A, Steen, Derrick, Theys, Fleur, Hammet, Helen, Tsimiklis, Daniel J, Park, Bernard J, Pope, Ryszard, Slezak, Agnieszka, Stembalska, Karolina, Pesz, Nataliya, Kitsera, Aleksandra, Siekierzynska, Melissa C, Southey, and Aleksander, Myszka
Subjects: BRCA2 Protein, Ovarian Neoplasms, endocrine system diseases, BRCA1 Protein, founder mutations, High-Throughput Nucleotide Sequencing, Breast Neoplasms, BRCA1, BRCA2, genetic testing, breast cancer, ovarian cancer, Humans, Female, Genetic Predisposition to Disease, Poland, skin and connective tissue diseases, Ukraine, Germ-Line Mutation, Research Paper, genetic susceptibility
Abstract: Purpose To characterize the spectrum of BRCA1 and BRCA2 pathogenic germline variants in women from south-west Poland and west Ukraine affected with breast or ovarian cancer. Testing in women at high risk of breast and ovarian cancer in these regions is currently mainly limited to founder mutations. Methods Unrelated women affected with breast and/or ovarian cancer from Poland (n = 337) and Ukraine (n = 123) were screened by targeted sequencing. Excluded from targeted sequencing were 34 Polish women who had previously been identified as carrying a founder mutation in BRCA1. No prior testing had been conducted among the Ukrainian women. Thus, this study screened BRCA1 and BRCA2 in the germline DNA of 426 women in total. Results We identified 31 and 18 women as carriers of pathogenic/likely pathogenic (P/LP) genetic variants in BRCA1 and BRCA2, respectively. We observed five BRCA1 and eight BRCA2 P/LP variants (13/337, 3.9%) in the Polish women. Combined with the 34/337 (10.1%) founder variants identified prior to this study, the overall P/LP variant frequency in the Polish women was thus 14% (47/337). Among the Ukrainian women, 16/123 (13%) women were identified as carrying a founder mutation and 20/123 (16.3%) were found to carry non-founder P/LP variants (10 in BRCA1 and 10 in BRCA2). Conclusions These results indicate that genetic testing in women at high risk of breast and ovarian cancer in Poland and Ukraine should not be limited to founder mutations. Extended testing will enhance risk stratification and management for these women and their families.
Published: 2020

17. Exposure to household air pollution over 10 years is related to asthma and lung function decline

Author: Peter Frith, Garun S. Hamilton, Dinh S Bui, John Burgess, Paul S. Thomas, Jennie Hui, Jennifer L. Perret, Shyamali C. Dharmage, Caroline J Lodge, Gayan Bowatte, Aung Ko Win, E. Haydn Walters, Michael J. Abramson, Xin Dai, Helen Tsimiklis, Adrian J. Lowe, and Graham G. Giles
Subjects: Pulmonary and Respiratory Medicine, Adult, Air pollution, medicine.disease_cause, Tobacco smoke, law.invention, Atopy, GSTP1, law, Environmental health, Air Pollution, medicine, Humans, Cooking, Prospective Studies, Adverse effect, Lung, Lung function, Asthma, business.industry, Middle Aged, medicine.disease, Air Pollution, Indoor, Ventilation (architecture), business
Abstract: IntroductionWe investigated if long-term household air pollution (HAP) is associated with asthma and lung function decline in middle-aged adults, and whether these associations were modified by glutathione S-transferase (GST) gene variants, ventilation and atopy.Materials and methodsProspective data on HAP (heating, cooking, mould and smoking) and asthma were collected in the Tasmanian Longitudinal Health Study (TAHS) at mean ages 43 and 53 years (n=3314). Subsamples had data on lung function (n=897) and GST gene polymorphisms (n=928). Latent class analysis was used to characterise longitudinal patterns of exposure. Regression models assessed associations and interactions.ResultsWe identified seven longitudinal HAP profiles. Of these, three were associated with persistent asthma, greater lung function decline and % reversibility by age 53 years compared with the “Least exposed” reference profile for those who used reverse-cycle air conditioning, electric cooking and no smoking. The “All gas” (OR 2.64, 95% CI 1.22–5.70), “Wood heating/smoking” (OR 2.71, 95% CI 1.21–6.05) and “Wood heating/gas cooking” (OR 2.60, 95% CI 1.11–6.11) profiles were associated with persistent asthma, as well as greater lung function decline and % reversibility. Participants with the GSTP1 Ile/Ile genotype were at a higher risk of asthma or greater lung function decline when exposed compared with other genotypes. Exhaust fan use and opening windows frequently may reduce the adverse effects of HAP produced by combustion heating and cooking on current asthma, presumably through increasing ventilation.ConclusionsExposures to wood heating, gas cooking and heating, and tobacco smoke over 10 years increased the risks of persistent asthma, lung function decline and % reversibility, with evidence of interaction by GST genes and ventilation.
Published: 2020

18. Genetic testing in Poland and Ukraine: should comprehensive germline testing of BRCA1 and BRCA2 be recommended for women with breast and ovarian cancer?

Author: Aleksandra Siekierzynska, Ryszard Slezak, Melissa C. Southey, Daniel J. Park, Agnieszka Stembalska, Maria M. Sasiadek, Nataliya Kitsera, Helen Tsimiklis, Derrick Theys, Fleur Hammet, Pawel Karpinski, Jason A. Steen, Tu Nguyen-Dumont, Karolina Pesz, Aleksander Myszka, Hayane Akopyan, and Bernard J. Pope
Subjects: Oncology, 0303 health sciences, medicine.medical_specialty, medicine.diagnostic_test, business.industry, 030305 genetics & heredity, Genetic variants, General Medicine, medicine.disease, Germline, 03 medical and health sciences, Breast cancer, Internal medicine, Genetics, medicine, Genetic predisposition, business, Ovarian cancer, Founder mutation, Likely pathogenic, 030304 developmental biology, Genetic testing
Abstract: Purpose To characterize the spectrum of BRCA1 and BRCA2 pathogenic germline variants in women from south-west Poland and west Ukraine affected with breast or ovarian cancer. Testing in women at high risk of breast and ovarian cancer in these regions is currently mainly limited to founder mutations. Methods Unrelated women affected with breast and/or ovarian cancer from Poland (n = 337) and Ukraine (n = 123) were screened by targeted sequencing. Excluded from targeted sequencing were 34 Polish women who had previously been identified as carrying a founder mutation in BRCA1. No prior testing had been conducted among the Ukrainian women. Thus, this study screened BRCA1 and BRCA2 in the germline DNA of 426 women in total. Results We identified 31 and 18 women as carriers of pathogenic/likely pathogenic (P/LP) genetic variants in BRCA1 and BRCA2, respectively. We observed five BRCA1 and eight BRCA2 P/LP variants (13/337, 3.9%) in the Polish women. Combined with the 34/337 (10.1%) founder variants identified prior to this study, the overall P/LP variant frequency in the Polish women was thus 14% (47/337). Among the Ukrainian women, 16/123 (13%) women were identified as carrying a founder mutation and 20/123 (16.3%) were found to carry non-founder P/LP variants (10 in BRCA1 and 10 in BRCA2). Conclusions These results indicate that genetic testing in women at high risk of breast and ovarian cancer in Poland and Ukraine should not be limited to founder mutations. Extended testing will enhance risk stratification and management for these women and their families.
Published: 2020
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19. Is RNASEL:p.Glu265* a modifier of early-onset breast cancer risk for carriers of high-risk mutations?

Author: Graham G. Giles, Melissa C. Southey, Andrew Lonie, David E. Goldgar, Zhi Ling Teo, John L. Hopper, Ingrid Winship, Helen Tsimiklis, Khalid Mahmood, Tu Nguyen-Dumont, Maryam Mahmoodi, Fleur Hammet, Miroslav Kapuscinski, Alexis Roberge, Bernard J. Pope, and Daniel J. Park
Subjects: Adult, 0301 basic medicine, Oncology, Heterozygote, Cancer Research, medicine.medical_specialty, PALB2, Breast Neoplasms, RNASEL:P.Glu265, medicine.disease_cause, urologic and male genital diseases, lcsh:RC254-282, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Germline mutation, Internal medicine, Endoribonucleases, Genetics, medicine, Humans, Genetic Predisposition to Disease, Modifier risk gene, Age of Onset, skin and connective tissue diseases, Allele frequency, Genotyping, BRCA2 Protein, Mutation, BRCA1 Protein, business.industry, Australia, Middle Aged, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Pedigree, Early-onset cancer, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Age of onset, business, Research Article
Abstract: Background Breast cancer risk for BRCA1 and BRCA2 pathogenic mutation carriers is modified by risk factors that cluster in families, including genetic modifiers of risk. We considered genetic modifiers of risk for carriers of high-risk mutations in other breast cancer susceptibility genes. Methods In a family known to carry the high-risk mutation PALB2:c.3113G>A (p.Trp1038*), whole-exome sequencing was performed on germline DNA from four affected women, three of whom were mutation carriers. Results RNASEL:p.Glu265* was identified in one of the PALB2 carriers who had two primary invasive breast cancer diagnoses before 50 years. Gene-panel testing of BRCA1, BRCA2, PALB2 and RNASEL in the Australian Breast Cancer Family Registry identified five carriers of RNASEL:p.Glu265* in 591 early onset breast cancer cases. Three of the five women (60%) carrying RNASEL:p.Glu265* also carried a pathogenic mutation in a breast cancer susceptibility gene compared with 30 carriers of pathogenic mutations in the 586 non-carriers of RNASEL:p.Glu265* (5%) (p
Published: 2018
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20. Targeted massively parallel sequencing characterises the mutation spectrum of PALB2 in breast and ovarian cancer cases from Poland and Ukraine

Author: Maria M. Sasiadek, Nataliya Kitsera, Ryszard Slezak, Melissa C. Southey, Bernard J. Pope, Aleksandra Siekierzynska, Pawel Karpinski, Hayane Akopyan, Daniel J. Park, Tu Nguyen-Dumont, Helen Tsimiklis, Aleksander Myszka, and Fleur Hammet
Subjects: 0301 basic medicine, Adult, Cancer Research, Massively parallel sequencing, PALB2, Population, DNA Mutational Analysis, Breast Neoplasms, Biology, Bioinformatics, 03 medical and health sciences, Breast cancer, Germline mutation, Ovarian cancer, Genetics, Genetic predisposition, medicine, Genetic susceptibility, Humans, Genetic Predisposition to Disease, education, Genetics (clinical), Genetic testing, Ovarian Neoplasms, education.field_of_study, medicine.diagnostic_test, Cancer, High-Throughput Nucleotide Sequencing, Middle Aged, medicine.disease, 3. Good health, 030104 developmental biology, Oncology, Mutation, Original Article, Female, Poland, Fanconi Anemia Complementation Group N Protein, Ukraine
Abstract: Loss-of-function germline mutations in the PALB2 gene are associated with an increase of breast cancer risk. The purpose of this study was to characterise the spectrum of PALB2 mutations in women affected with breast or ovarian cancer from South-West Poland and West Ukraine. We applied Hi-Plex, an amplicon-based enrichment method for targeted massively parallel sequencing, to screen the coding exons and proximal intron-exon junctions of PALB2 in germline DNA from unrelated women affected with breast cancer (n = 338) and ovarian cancer (n = 89) from Poland (n = 304) and Ukraine (n = 123). These women were at high-risk of carrying a genetic predisposition to breast and/or ovarian cancer due to a family history and/or early-onset disease. Targeted-sequencing identified two frameshift deletions: PALB2:c.509_510del; p.R170Ifs in three women affected with breast cancer and PALB2:c.172_175del;p.Q60Rfs in one woman affected with ovarian cancer. A number of other previously described missense (some predicted to be damaging by PolyPhen-2 and CADD) and synonymous mutations were also identified in this population. This study is consistent with previous reports that PALB2:c.509_510del and PALB2:c.172_175del are recurrent mutations associated with breast cancer predisposition in Polish women with a family history of the disease. Our study contributes to the accumulating evidence indicating that PALB2 should be included in genetic testing for breast cancer susceptibility in these populations to enhance risk assessment and management of women at high-risk of developing breast cancer. This data could also contribute to ongoing work that is assessing the possible association between ovarian cancer risk and PALB2 mutations for which there is currently no evidence.
Published: 2017

21. Rare germline genetic variants and risk of aggressive prostate cancer

Author: Derrick Theys, Melissa C. Southey, Gianluca Severi, Helen Tsimiklis, Fleur Hammet, Daniel J. Park, Tu Nguyen-Dumont, Damien M Bolton, Roger L. Milne, Maryam Mahmoodi, Bernard J. Pope, Jason A. Steen, Khalid Mahmood, Robert J. MacInnis, and Graham G. Giles
Subjects: Oncology, Male, Cancer Research, medicine.medical_specialty, Genotype, Context (language use), Disease, urologic and male genital diseases, Cohort Studies, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Germline mutation, Internal medicine, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Germ-Line Mutation, Genetic testing, Aged, BRCA2 Protein, medicine.diagnostic_test, business.industry, Prostate, Prostatic Neoplasms, Middle Aged, Prostate-Specific Antigen, medicine.disease, Prostate-specific antigen, Germ Cells, 030220 oncology & carcinogenesis, business
Abstract: Few genetic risk factors have been demonstrated to be specifically associated with aggressive prostate cancer (PrCa). Here, we report a case-case study of PrCa comparing the prevalence of germline pathogenic/likely pathogenic (P/LP) genetic variants in 787 men with aggressive disease and 769 with nonaggressive disease. Overall, we observed P/LP variants in 11.4% of men with aggressive PrCa and 9.8% of men with nonaggressive PrCa (two-tailed Fisher's exact tests, P = .28). The proportion of BRCA2 and ATM P/LP variant carriers in men with aggressive PrCa exceeded that observed in men with nonaggressive PrCa; 18/787 carriers (2.3%) and 4/769 carriers (0.5%), P = .004, and 14/787 carriers (0.02%) and 5/769 carriers (0.01%), P = .06, respectively. Our findings contribute to the extensive international effort to interpret the genetic variation identified in genes included on gene-panel tests, for which there is currently an insufficient evidence-base for clinical translation in the context of PrCa risk.
Published: 2019

22. Abstract PS7-04: Population-based estimates of breast cancer risk for germline pathogenic variants identified by gene-panel testing: An Australian perspective

Author: Rebecca Harris, Scott Grist, Nicholas Pachter, Catherine Speechly, Fleur Hammet, Amanda M. Willis, Eric E. Schadt, Daniel J. Park, April Morrow, Melissa C. Southey, John L. Hopper, Nicola K. Poplawski, Derrick Theys, Robert Sebra, Paul A. James, Anne Laure Renault, Amanda Rewse, Paul Lacaze, Helen Tsimiklis, John J McNeil, Maryam Mahmoodi, Alison H. Trainer, Moeen Riaz, Tu Nguyen-Dumont, James G. Dowty, Ingrid Winship, Katherine L. Tucker, Judy Kirk, and Jason A. Steen
Subjects: Genetics, Cancer Research, Breast cancer, Oncology, Gene panel, Perspective (graphical), medicine, Population based, Biology, medicine.disease, Germline
Abstract: BRA-STRAP is an Australia-wide study of breast cancer predisposition that brings together gene-panel data from 30,000 adult Australian women of all ages, across the breast cancer risk spectrum, with and without a diagnosis of breast cancer. The “BRA-STRAP panel” includes 24 genes* that are involved in, or putatively associated with, predisposition to breast and/or ovarian cancer. Despite insufficient evidence for clinical translation for some of these genes, all 24 are commonly included on panel tests for breast cancer predisposition. We present findings from the population-based case-control sub-study of BRA-STRAP, which involved 1451 women diagnosed with breast cancer and 857 age-matched controls participating in the Australian Breast Cancer Family Registry (ABCFR), and 6101 healthy, elderly Australian women enrolled in the ASPREE study. These analyses focus on rare genetic variants predicted to lead to loss of function and/or classified as pathogenic/likely pathogenic (P/LP) in ClinVar. Odds ratios (ORs) for their associations with breast cancer were estimated by aggregating genetic variants for each gene. For the women diagnosed with breast cancer, the median age at diagnosis (inter-quartile range, IQR) was 40.0 (14.0) years and the overall frequency of P/LP variant carriers across all genes was 156/1451 (10.8%). The median age (IQR) of the ABCFR and ASPREE controls were 39.4 (14.9) and 73.9 (5.8) years, respectively. The frequencies of P/LP variant carriers were 33/857 (3.9%) and 268/6101 (4.4%) in the ABCFR and ASPREE controls, respectively. We combined both control datasets and, after adjusting for age and other potential confounders, the ORs associated with P/LP variants in BRCA1 and BRCA2 were 4.1 [95% confidence interval (CI): 1.8-10.2] and 2.9 [95% CI: 1.5-6], respectively. We also found that the OR for P/LP variants in ATM was 4.0 [95% CI: 1.5-10.4] and the OR for P/LP variants in PALB2 was 2.2 [95% CI: 0.75-5.7] although this did not reach statistical significance. These results contribute to international efforts to refine the breast cancer risk estimates for genetic variants identified from population-based screening of unselected women using genes that are included on panel tests and thought to be potentially breast cancer predisposition genes.The case-control-family design of the ABCFR will also allow us to estimate the age specific cumulative risk (penetrance) of these genetic variants, which is important for genetic counselling and the clinical management of carrier families. *ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, FANCM, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, RECQL, STK11 and TP53 Citation Format: Tu Nguyen-Dumont, James Dowty, Katherine Tucker, Judy Kirk, Paul James, Alison Trainer, Ingrid Winship, Nicholas Pachter, Nicola Poplawski, Scott Grist, Daniel J Park, Anne-Laure Renault, Fleur Hammet, Maryam Mahmoodi, Helen Tsimiklis, Jason A Steen, Derrick Theys, Amanda Rewse, Amanda Willis, April Morrow, Catherine Speechly, Rebecca Harris, Moeen Riaz, Robert Sebra, Eric Schadt, Paul Lacaze, John McNeil, John L Hopper, Melissa C Southey. Population-based estimates of breast cancer risk for germline pathogenic variants identified by gene-panel testing: An Australian perspective [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-04.
Published: 2021
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23. Mould-sensitized adults have lower Th2 cytokines and a higher prevalence of asthma than those sensitized to other aeroallergens

Author: Melanie C. Matheson, Rangi Kandane-Rathnayake, Mimi L.K. Tang, Melissa C. Southey, Shyamali C. Dharmage, Helen Tsimiklis, Julie A. Simpson, John L. Hopper, Graham G. Giles, Jeanette C. Reece, Iain Feather, Stephen Morrison, and Eugene Haydn Walters
Subjects: Hypersensitivity, Immediate, Male, 0301 basic medicine, Allergy, Immunology, Population, medicine.disease_cause, Atopy, 03 medical and health sciences, Th2 Cells, Allergen, Blood serum, Risk Factors, Odds Ratio, Prevalence, Humans, Immunology and Allergy, Medicine, Longitudinal Studies, education, Asthma, House dust mite, education.field_of_study, biology, business.industry, Aeroallergen, Allergens, biology.organism_classification, medicine.disease, 030104 developmental biology, Cytokines, Female, Immunization, business
Abstract: Background: Evidence suggests that specific allergen sensitizations are associated with different allergic diseases which may reflect different underlying immune profiles. We aimed to examine the cytokine profiles of individuals sensitized to eight common aeroallergens. Methods: We used data from the Tasmanian Longitudinal Health Study a population-based cohort study of 45-year-olds. Serum cytokines (IL-4, IL-5, IL-6, IL-8, IL-10, TNF-α) were measured in 1157 subjects using the LINCOplex assays. Participants underwent skin prick testing for house dust mite, cat, grasses and moulds. Multivariable linear regression was used to compare serum cytokine levels between sensitized and nonatopic subjects. Results: The prevalence of allergic sensitization to any aeroallergen was 51% (95% CI 47–54). Being sensitized to any aeroallergen was strongly associated with current asthma (OR = 3.7, 95% CI 2.6–5.3), and being sensitized to any moulds was associated with a very high risk of current asthma (OR = 6.40, 95% CI 4.06–10.1). The geometric mean (GM) levels of Th2 cytokines (IL-4, IL-5 and IL-6) for adults sensitized to Cladosporium were significantly lower than the levels for nonatopic individuals (IL-4 ratio of GMs = 0.25, 95% CI 0.10–0.62, P = 0.003; IL-5 GM = 0.55, 95% CI 0.30–0.99, P = 0.05; and IL-6 GM = 0.50, 95% CI 0.24–1.07, P = 0.07). Individuals sensitized to other aeroallergens all showed elevated Th2 cytokine levels. Conclusion: Our study is the first large population-based study to demonstrate reduced Th2 cytokines levels in people sensitized to mould. Underlying biological mechanisms driving allergic inflammatory responses in adults sensitized to moulds may differ from those sensitized to other aeroallergens. These findings suggest that it may be necessary to tailor treatments in individuals sensitized to moulds compared with other aeroallergens in order to optimize outcomes.
Published: 2016
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24. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Author: Javier Benitez, Marie Stenmark-Askmalm, Susan L. Neuhausen, Pascal Guénel, Jane Carpenter, Christine B. Ambrosone, Dominique Stoppa-Lyonnet, Nadine Tung, Gad Rennert, Stephen J. Chanock, Andrew K. Godwin, Regina M. Santella, Brita Arver, Karoline Kuchenbaecker, Kamila Czene, Vessela N. Kristensen, Natalia Bogdanova, Nazneen Rahman, Jianjun Liu, Federico Canzian, Hoda Anton-Culver, Maya Ghoussaini, Mark E. Robson, Sue K. Park, Manjeet K. Bolla, Roger L. Milne, Veli-Matti Kosma, Siranoush Manoukian, Angela Cox, Daniel F. Schmidt, Kay-Tee Khaw, Rosario Tumino, Melissa C. Southey, Ramunas Janavicius, Irene Konstantopoulou, Carl Blomqvist, John L. Hopper, Sue Healey, Christine Rappaport, Marco Montagna, SA Gayther, Heather Eliassen, Carolien H.M. van Deurzen, Jacques Simard, Emiel J. Rutgers, Jonine Figueroa, Maria A. Caligo, Volker Arndt, Sylvie Mazoyer, Diana Eccles, M.J. Hooning, Antoinette Hollestelle, Mary B. Daly, Robert Winqvist, Antonis C. Antoniou, Patricia A. Ganz, Orland Diez, Priyanka Sharma, Ana Osorio, Daniel Barrowdale, Loic Le Marchand, Drakoulis Yannoukakos, Elinor J. Sawyer, Conxi Lázaro, Soo-Hwang Teo, Penny Soucy, Paolo Radice, John W. M. Martens, Steve Ellis, David E. Goldgar, Anna Jakubowska, Maria Kabisch, Raymonda Varon-Mateeva, Diether Lambrechts, Paul D.P. Pharoah, Leigha Senter, Anna González-Neira, Cecilia M. Dorfling, Brian E. Henderson, Rulla M. Tamimi, Sara Margolin, Susan M. Gapstur, Ian Tomlinson, Thérèse Truong, Robert A.E.M. Tollenaar, Amanda E. Toland, Anna Marie Mulligan, Irene L. Andrulis, Isabelle Romieu, Monica Barile, Florentia Fostira, Johanna Rantala, Enes Makalic, Eitan Friedman, Zhaoming Wang, Mark H. Greene, Noralane M. Lindor, Julie M. Cunningham, Riccardo Dolcetti, Steven N. Hart, Mary Beth Terry, Jenny Chang-Claude, Austin Miller, Georgia Chenevix-Trench, Asta Försti, Kathleen E. Malone, Paolo Peterlongo, Lothar Haeberle, Celine M. Vachon, Elizabeth J. van Rensburg, Michael Jones, Laima Tihomirova, Penelope Miron, Eunjung Lee, María José Sánchez, Hatef Darabi, Frans B. L. Hogervorst, Matthias W. Beckmann, Edith Olah, Annika Lindblom, Phuong L. Mai, Emily Hallberg, Alison M. Dunning, Kathleen Claes, Esther M. John, Sofia Khan, David J. Hunter, Kristiina Aittomäki, Katherine L. Nathanson, Lars Beckmann, Stephanie V. Blank, Wei Zheng, Olufunmilayo I. Olopade, Heli Nevanlinna, Miguel de la Hoya, Olga M. Sinilnikova, Bruce Poppe, Catherine M. Phelan, S. Lindstrom, Stig E. Bojesen, Curtis Olswold, Fredrick R. Schumacher, Janet E. Olson, Tuomas Heikkinen, Judy Garber, Fergus J. Couch, Tara M. Friebel, Isabel dos-Santos-Silva, Douglas F. Easton, Song Yao, Dieter Flesch-Janys, Hans Ehrencrona, Simon S. Cross, Rodney J. Scott, Kenneth Offit, Petra H.M. Peeters, Clare Turnbull, Taru A. Muranen, William J. Tapper, Trinidad Caldés, Jenny Lester, Robert L. Nussbaum, Paul A. James, Marike Gabrielson, Susan M. Domchek, Mads Thomassen, Marilie D. Gammon, Susan L. Slager, Graham G. Giles, Silje Nord, Hans Wildiers, Hiltrud Brauch, Gustavo Mendoza-Fandiño, Christopher A. Haiman, Martine Dumont, Mark S. Goldberg, Bernardo Bonanni, Jirong Long, Kyriaki Michailidou, Ute Hamann, Wendy K. Chung, Marc J. Gunter, Mia M. Gaudet, Keith Humphreys, Per Hall, Yuan C. Ding, Simona Agata, Julia A. Knight, Robert Pilarski, Claudine Isaacs, Alvaro A.N. Monteiro, Montserrat Garcia-Closas, Rosa B. Barkardottir, Beth Y. Karlan, Uffe Birk Jensen, Arif B. Ekici, Evgeny N. Imyanitov, Alex Teulé, Anne-Marie Gerdes, Frederik Marme, Debra Frost, Anthony J. Swerdlow, Yon Ko, Xiaohong R. Yang, Jan Lubinski, Peter A. Fasching, Lesley McGuffog, Jacek Gronwald, Katri Pylkäs, Banu Arun, Josef Herzog, Gord Glendon, Doris Steinemann, Tomasz Huzarski, Peter Kraft, Anja Rudolph, Arto Mannermaa, Habibul Ahsan, Christian F. Singer, Rita K. Schmutzler, Julian Peto, Giski Ursin, Shan Wang-Gohrke, Andrea L. Richardson, Jeffrey N. Weitzel, Børge G. Nordestgaard, Marjanka K. Schmidt, Alice S. Whittemore, Hermann Brenner, Barbara Burwinkel, D Thompson, Csilla I. Szabo, M. Pilar Zamora, Janna Lilyquist, Muhammad G. Kibriya, Yael Laitman, Helen Tsimiklis, W. D. Foulkes, Thomas Hansen, Francesca Damiola, Robert N. Hoover, Ava Kwong, Alfons Meindl, Siddhartha Kar, Manuel R. Teixeira, Elisabete Weiderpass, Bernard Peissel, Saundra S. Buys, Peter Devilee, Unión Europea. Comisión Europea. 7 Programa Marco, Cancer Research UK (Reino Unido), National Institutes of Health (Estados Unidos), Canadian Institutes of Health Research, Florida Breast Cancer Foundation (Estados Unidos), Dunning, Alison [0000-0001-6651-7166], Ghoussaini, Maya [0000-0002-2415-2143], Khaw, Kay-Tee [0000-0002-8802-2903], Thompson, Deborah [0000-0003-1465-5799], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Medical Oncology, Obstetrics & Gynecology, Pathology, Cell biology, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, Department of Oncology, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, and [ 1 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA [ 2 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA [ 3 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England [ 4 ] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Canc Epidemiol Program, Tampa, FL 33612 USA [ 5 ] Radiumhosp, Oslo Univ Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway [ 6 ] IRCCS, IOV, Immunol & Mol Oncol Unit, I-20133 Padua, Italy [ 7 ] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA [ 8 ] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA [ 9 ] Univ Chicago, Dept Med & Human Genet, Chicago, IL 60637 USA [ 10 ] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki 00029, Finland [ 11 ] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA [ 12 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada [ 13 ] Univ Toronto, Dept Mol Genet, Toronto, ON M5B 1W8, Canada [ 14 ] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5B 1W8, Canada [ 15 ] Univ Calif Irvine, Dept Epidemiol, Irvine, CA 92697 USA [ 16 ] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany [ 17 ] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA [ 18 ] Karolinska Univ Hosp, Dept Oncol, SE-17176 Stockholm, Sweden [ 19 ] Ist Europeo Oncol, Div Canc Prevent & Genet, I-20141 Milan, Italy [ 20 ] Landspitali Univ Hosp, Dept Pathol, IS-101 Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 21 ] Univ Iceland, Sch Med, IS-101 Reykjavik, Iceland [ 22 ] Inst Qual & Efficiency Hlth Care IQWiG, D-50670 Cologne, Germany [ 23 ] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Breast Ctr Franconia, Dept Gynecol & Obstet,Univ Hosp Erlangen, D-91054 Erlangen, Germany [ 24 ] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Human Canc Genet Program, Madrid 28029, Spain [ 25 ] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Genotyping Unit CeGen, Madrid 28029, Spain [ 26 ] Biomed Network Rare Dis CIBERER, Madrid 28029, Spain [ 27 ] NYU, Sch Med, NYU Womens Canc Program, New York, NY 10016 USA [ 28 ] Univ Helsinki, Dept Oncol, FI-00029 Helsinki, Finland [ 29 ] Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland [ 30 ] Hannover Med Sch, Dept Radiat Oncol, D-30625 Hannover, Germany [ 31 ] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, DK-2730 Herlev, Denmark [ 32 ] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany [ 33 ] Univ Tubingen, D-72074 Tubingen, Germany [ 34 ] German Canc Res Ctr, Div Prevent Oncol, D-69120 Heidelberg, Germany [ 35 ] Natl Ctr Tumor Dis NCT, D-69120 Heidelberg, Germany [ 36 ] Heidelberg Univ, Dept Obstet & Gynecol, D-69120 Heidelberg, Germany [ 37 ] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA [ 38 ] IdISSC, Hosp Clin San Carlos, Mol Oncol Lab, Madrid 28040, Spain [ 39 ] Univ Pisa, Dept Lab Med, Sect Genet Oncol, I-56126 Pisa, Italy [ 40 ] Univ Hosp Pisa, I-56126 Pisa, Italy [ 41 ] German Canc Res Ctr, Genom Epidemiol Grp, D-69120 Heidelberg, Germany [ 42 ] Univ Sydney, Westmead 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dHebron, VHIO, Oncogenet Grp, Barcelona 08035, Spain [ 56 ] Univ Autonoma Barcelona, Barcelona 08035, Spain [ 57 ] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA [ 58 ] CRO Aviano Natl Canc Inst, Canc Bioimmunotherapy Unit, I-33081 Aviano, Italy [ 59 ] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA [ 60 ] Univ Pretoria, Dept Genet, ZA-0007 Pretoria, South Africa [ 61 ] Univ London London Sch Hyg & Trop Med, Dept Non Communicable Dis Epidemiol, Keppel St, London WC1E 7HT, England [ 62 ] Ctr Hosp Univ Quebec, Canc Genom Lab, Quebec City, PQ G1V 4G2, Canada [ 63 ] Univ Laval, Quebec City, PQ G1V 4G2, Canada [ 64 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England [ 65 ] Univ Southampton, Southampton Univ Hosp, Fac Med, Southampton SO16 6YD, Hants, England [ 66 ] Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden [ 67 ] Univ Lund Hosp, Dept Clin Genet, SE-22185 Lund, Sweden [ 68 ] 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Malaya, Med Ctr, Canc Res Inst, Fac Med, Kuala Lumpur 50603, Malaysia [ 188 ] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA [ 189 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark [ 190 ] Latvian Biomed Res & Study Ctr, LV-1067 Riga, Latvia [ 191 ] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA [ 192 ] Leiden Univ, Med Ctr, Dept Surg Oncol, NL-2333 ZC Leiden, Netherlands [ 193 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England [ 194 ] Univ Oxford, Oxford Biomed Res Ctr, Oxford OX3 7BN, England [ 195 ] IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Genet Counseling Unit, Barcelona 08908, Spain [ 196 ] Civ MP Arezzo Hosp, Canc Registry, I-97100 Asp Ragusa, Italy [ 197 ] Civ MP Arezzo Hosp, Histopathol Unit, I-97100 Asp Ragusa, Italy [ 198 ] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA [ 199 ] Inst Populat Based Canc Res, Canc Registry Norway, N-0304 Oslo, Norway [ 200 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Subjects: 0301 basic medicine, Oncology, General Physics and Astronomy, Genome-wide association study, Cyclophilins, Breast cancer, 3123 Gynaecology and paediatrics, Risk Factors, Brjóstakrabbamein, Genotype, BRCA2 MUTATION CARRIERS, Medicine and Health Sciences, CONFER SUSCEPTIBILITY, skin and connective tissue diseases, Cancer, GENE-EXPRESSION, Genetics, RISK, tRNA Methyltransferases, Multidisciplinary, Genome, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Loci, BRCA1 Protein, Chromosome Mapping, COMMON VARIANTS, IDENTIFY, PANCREATIC-CANCER, 3. Good health, Multidisciplinary Sciences, Biological sciences, Receptors, Estrogen, Chromosomes, Human, Pair 2, Science & Technology - Other Topics, Female, NAF12, medicine.medical_specialty, Heterozygote, Science, 3122 Cancers, Locus (genetics), Breast Neoplasms, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Pancreatic cancer, MD Multidisciplinary, medicine, Genetic predisposition, Journal Article, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, Cancer och onkologi, Science & Technology, VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762, General Chemistry, Arfgengi, medicine.disease, TRNA Methyltransferases, VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762, 030104 developmental biology, Cancer and Oncology, Expression quantitative trait loci, Mutation, TELOMERE LENGTH, 3111 Biomedicine, Gene expression, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Genome-Wide Association Study
Abstract: Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P, B.C.A.C. was funded through a European Community Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS); Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692); the National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), R01 grants (CA128978, CA176785, CA192393), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative); the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Breast Cancer Res. Foundation, and the Ovarian Cancer Research Fund. CIMBA genotyping was supported by National Institutes of Health grant (CA128978); the Department of Defence (W81XWH-10-1-0341); and the Breast Cancer Res. Foundation. CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. This study made use of data generated by the Wellcome Trust Case Control consortium. Functional studies were supported by the Florida Breast Cancer Foundation. A full description of funding and acknowledgments is provided in Supplementary Note 1.
Published: 2018
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25. FANCM and RECQL genetic variants and breast cancer susceptibility: relevance to South Poland and West Ukraine

Author: Nataliya Kitsera, Melissa C. Southey, Pawel Karpinski, Aleksander Myszka, Maria M. Sasiadek, Helen Tsimiklis, Ryszard Slezak, Fleur Hammet, Tu Nguyen-Dumont, Aleksandra Siekierzynska, Hayane Akopyan, Daniel J. Park, and Bernard J. Pope
Subjects: 0301 basic medicine, Oncology, medicine.disease_cause, 0302 clinical medicine, FANCM, Gene Frequency, Risk Factors, Gene panel testing, Genetics (clinical), Aged, 80 and over, Ovarian Neoplasms, Mutation, RecQ Helicases, medicine.diagnostic_test, Exons, Middle Aged, Pedigree, 3. Good health, RECQL, Codon, Nonsense, 030220 oncology & carcinogenesis, Female, Familial breast cancer, Ukraine, Research Article, Adult, lcsh:Internal medicine, medicine.medical_specialty, lcsh:QH426-470, Nonsense mutation, Breast Neoplasms, White People, Frameshift mutation, Young Adult, 03 medical and health sciences, Breast cancer, Internal medicine, Genetics, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, lcsh:RC31-1245, Aged, Genetic testing, business.industry, DNA Helicases, Genetic Variation, Cancer, medicine.disease, lcsh:Genetics, Breast cancer predisposition, 030104 developmental biology, Case-Control Studies, Poland, business
Abstract: Background FANCM and RECQL have recently been reported as breast cancer susceptibility genes and it has been suggested that they should be included on gene panel tests for breast cancer predisposition. However, the clinical value of testing for mutations in RECQL and FANCM remains to be determined. In this study, we have characterised the spectrum of FANCM and RECQL mutations in women affected with breast or ovarian cancer from South-West Poland and West Ukraine. Methods We applied Hi-Plex, an amplicon-based enrichment method for targeted massively parallel sequencing, to screen the coding exons and proximal intron-exon junctions of FANCM and RECQL in germline DNA from unrelated women affected with breast cancer (n = 338) and ovarian cancer (n = 89) from Poland (n = 304) and Ukraine (n = 123). These women were at high-risk of carrying a genetic predisposition to breast and/or ovarian cancer due to a family history and/or early-onset disease. Results Among 427 women screened, we identified one carrier of the FANCM:c.1972C > T nonsense mutation (0.23%), and two carriers of the frameshift insertion FANCM:c.1491dup (0.47%). None of the variants we observed in RECQL were predicted to be loss-of-function mutations by standard variant effect prediction tools. Conclusions Our study of the Polish and Ukrainian populations has identified a carrier frequency of truncating mutations in FANCM consistent with previous reports. Although initial reports suggesting that mutations in RECQL could be associated with increased breast cancer risk included women from Poland and identified the RECQL:c.1667_1667 + 3delAGTA mutation in 0.23–0.35% of breast cancer cases, we did not observe any carriers in our study cohort. Continued screening, both in research and diagnostic settings, will enable the accumulation of data that is needed to establish the clinical utility of including RECQL and FANCM on gene panel tests. Electronic supplementary material The online version of this article (10.1186/s12881-018-0524-x) contains supplementary material, which is available to authorized users.
Published: 2018
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26. Novel associations between blood DNA methylation and body mass index in middle-Aged and older adults

Author: Daniel D. Buchanan, Ellen W. Demerath, Gianluca Severi, Daniel F. Schmidt, Steve Nguyen, Weihua Guan, Julie K. Bassett, Pierre Antoine Dugué, Helen Tsimiklis, Graham G. Giles, Jihoon E. Joo, Dallas R. English, Melissa C. Southey, Robert J. MacInnis, Y. M. Geurts, James S. Pankow, Enes Makalic, John L. Hopper, Ee Ming Wong, Roger L. Milne, Chol-Hee Jung, Laura Baglietto, Allison M. Hodge, Liesel M. FitzGerald, and Megan L. Grove
Subjects: 0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, Cross-sectional study, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Body Mass Index, 03 medical and health sciences, Insulin resistance, Endocrinology, Internal medicine, Neoplasms, medicine, Humans, Gene Regulatory Networks, Epigenetics, Nutrition and Dietetics, Aged, business.industry, Confounding, Australia, Methylation, DNA, DNA Methylation, Middle Aged, medicine.disease, Diabetes and Metabolism, 030104 developmental biology, Cross-Sectional Studies, DNA methylation, Female, business, Body mass index, Cohort study, Genome-Wide Association Study
Abstract: There is increasing evidence of a relationship between blood DNA methylation and body mass index (BMI). We aimed to assess associations of BMI with individual methylation measures (CpGs) through a cross-sectional genome-wide DNA methylation association study and a longitudinal analysis of repeated measurements over time. Using the Illumina Infinium HumanMethylation450 BeadChip, DNA methylation measures were determined in baseline peripheral blood samples from 5361 adults recruited to the Melbourne Collaborative Cohort Study (MCCS) and selected for nested case–control studies, 2586 because they were subsequently diagnosed with cancer (cases) and 2775 as controls. For a subset of 1088 controls, these measures were repeated using blood samples collected at wave 2 follow-up, a median of 11 years later; weight was measured at both time points. Associations between BMI and blood DNA methylation were assessed using linear mixed-effects regression models adjusted for batch effects and potential confounders. These were applied to cases and controls separately, with results combined through fixed-effects meta-analysis. Cross-sectional analysis identified 310 CpGs associated with BMI with P
Published: 2018

27. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Author: Vesa Kataja, Aida Karina Dieffenbach, Chia-Ni Hsiung, Catherine S. Healey, Gie Hooi Tan, Soo Hwang Teo, Domenico Palli, Frederik Marme, Katri Pylkäs, Roger L. Milne, Jaana M. Hartikainen, Gord Glendon, Susan L. Slager, Chen-Yang Shen, Fredrick R. Schumacher, Daniel F. Schmidt, Suleeporn Sangrajrang, Kee Seng Chia, Lorna Gibson, Pascal Guénel, Alice S. Whittemore, Jenny Chang-Claude, Yu Tang Gao, Hidemi Ito, Simon S. Cross, Sofia Khan, Marie Sanchez, Daniel Vincent, Daniel Herrero, Nicola Miller, Antoinette Hollestelle, Caroline M. Seynaeve, Christopher A. Haiman, Hermann Brenner, Kay-Tee Khaw, Loris Bernard, Habibul Ahsan, Melissa C. Southey, David Van Den Berg, Martha J. Shrubsole, Daniel O. Stram, William Blot, Mel Maranian, Robert Winqvist, Keitaro Matsuo, John W. M. Martens, Heli Nevanlinna, Mia M. Gaudet, Anna Jakubowska, Christine D. Berg, Paul D.P. Pharoah, Jacques Simard, Manjeet K. Bolla, Dieter Flesch-Janys, Mark S. Goldberg, Paul Brennan, Ching Wan Chan, Sune F. Nielsen, Sara Lindström, Mitul Shah, Matthias W. Beckmann, Craig Luccarini, Jonathan Beesley, Kyriaki Michailidou, Paolo Peterlongo, Marc J. Gunter, Anna González-Neira, Ji Yeob Choi, Per Hall, Sarah Stewart-Brown, Keith Humphreys, Hui Cai, Kathleen E. Malone, Elinor J. Sawyer, Louise A. Brinton, Marjanka K. Schmidt, Xiao-Ou Shu, Barbara Perkins, Lotte Maxild Mortensen, Chiu-Chen Tseng, Hanne Meijers-Heijboer, Minouk J. Schoemaker, Keun-Young Yoo, Julia A. Knight, Alan Ashworth, Stig E. Bojesen, Kamila Czene, Artitaya Lophatananon, Graham G. Giles, S. Ahmed, Kazuo Tajima, Douglas F. Easton, Maria Kabisch, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Irene L. Andrulis, Clare Turnbull, Caroline Baynes, Christine B. Ambrosone, Jan Lubinski, Muriel A. Adank, A. Meindl, Taru A. Muranen, Siranoush Manoukian, Susan M. Gapstur, Natalia Bogdanova, Alexander Hein, Annika Lindblom, Nazneen Rahman, Annegien Broeks, Lothar Haeberle, Federico Canzian, G Pita, Ming-Feng Hou, Hiroji Iwata, Drakoulis Yannoukakos, Diana Torres, Vessela N. Kristensen, Peter Devilee, Qiuyin Cai, Christi J Asperen, John L. Hopper, Diether Lambrechts, Michael Lush, Hans Wildiers, Joe Dennis, Sandra L. Halverson, Carl Blomqvist, Erik Van Limbergen, Malin Sund, Daehee Kang, Grethe I. Grenaker Alnæs, Marilie D. Gammon, Ursula Eilber, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Kirsimari Aaltonen, Olivia Fletcher, Jonine D. Figueroa, Angela Cox, Pei Ei Wu, Maartje J. Hooning, Catriona McLean, Georgia Chenevix-Trench, Pornthep Siriwanarangsan, Malcolm W.R. Reed, Emily Hallberg, Sara Margolin, Volker Arndt, Montserrat Garcia-Closas, Francois Bacot, Rita K. Schmutzler, Julian Peto, David J. Hunter, Thomas Brüning, Katarzyna Jaworska, Christof Sohn, Børge G. Nordestgaard, Enes Makalic, Hatef Darabi, Barbara Burwinkel, Petra P.H. Peeters, J. Margriet Collée, Rongxi Yang, Robert N. Hoover, Eiliv Lund, Fergus J. Couch, Ute Hamann, Jirong Long, Wei Zheng, Sabine Behrens, Giske Ursin, Muhammad G. Kibriya, Claire Mulot, Laure Dossus, Helen Tsimiklis, Tomasz Huzarski, Peter Kraft, Anja Rudolph, Arto Mannermaa, Alison M. Dunning, Lisa B. Signorello, Valerie Gaborieau, Kenneth Muir, Anthony J. Swerdlow, Javier Benitez, Judith S. Brand, Sander Canisius, Hoda Anton-Culver, Veli-Matti Kosma, Thilo Dörk, Sten Cornelissen, Christa Stegmaier, Cheng Har Yip, Brian E. Henderson, Harald Surowy, Jingmei Li, Nur Aishah Taib, W. Ryan Diver, Carmel Apicella, Janet E. Olson, Kristiina Aittomäki, Celine M. Vachon, Regina M. Santella, Dimitrios Trichopoulos, Jianjun Liu, Nick Orr, Martine Dumont, Christian Sutter, Sue K. Park, Mikael Hartman, Susan L. Neuhausen, Hui Miao, M. Pilar Zamora, Anna H. Wu, Rob B. van der Luijt, Isabel dos-Santos-Silva, Graham Casey, Henrik Flyger, M. Rosario Alonso, Nuria Álvarez, Michael J. Kerin, Loic Le Marchand, Jose Ignacio Arias Perez, Mikael Eriksson, Esther M. John, Quinten Waisfisz, Qin Wang, Daniel C. Tessier, Paolo Radice, Robert A.E.M. Tollenaar, James McKay, Silje Nord, Hiltrud Brauch, José María Huerta, Stephen J. Chanock, Mervi Grip, Patrick Neven, Senno Verhoef, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Cardiothoracic Surgery, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Khaw, Kay-Tee [0000-0002-8802-2903], 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, and CCA - Oncogenesis
Subjects: Breast Neoplasms, Single-nucleotide polymorphism, Genome-wide association study, Biology, Research Support, Polymorphism, Single Nucleotide, N.I.H, Cohort Studies, brca1, Breast cancer, Research Support, N.I.H., Extramural, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, common variants, Journal Article, estrogen, chek2-asterisk-1100delc, Genetics, medicine, Humans, Genetic Predisposition to Disease, 1000 Genomes Project, Non-U.S. Gov't, genotype imputation, risk, Genetic association, Research Support, Non-U.S. Gov't, Chromatin binding, Extramural, Cancer, Microarray Analysis, confer susceptibility, medicine.disease, 3. Good health, ovarian-cancer, Genetic Loci, Case-Control Studies, alleles, Female, Imputation (genetics), Genome-Wide Association Study, metaanalysis
Abstract: Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1. ispartof: Nature Genetics vol:47 issue:4 pages:373-80 ispartof: location:United States status: published
Published: 2015
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28. Epigenome-wide methylation in DNA from peripheral blood as a marker of risk for breast cancer

Author: Graham G. Giles, Gianluca Severi, Catriona McLean, Helen Tsimiklis, Dallas R. English, Chol-Hee Jung, Andrew Lonie, Laura Baglietto, Melissa C. Southey, and John L. Hopper
Subjects: Adult, Epigenomics, Oncology, Cancer Research, medicine.medical_specialty, Melbourne Collaborative Cohort Study, Peripheral blood, Breast Neoplasms, Biology, Bioinformatics, Promoter Regions, Breast cancer, Genetic, Internal medicine, Biomarkers, Tumor, medicine, Humans, Epigenetics, Promoter Regions, Genetic, Aged, Neoplasm Staging, Tumor, Risk marker, DNA methylation, Case-Control Studies, CpG Islands, DNA Methylation, Female, Genome-Wide Association Study, Middle Aged, Cancer, Methylation, medicine.disease, CpG site, Human genome, Biomarkers
Abstract: Aberrant DNA methylation is a key feature of breast carcinoma. We aimed to test the association between breast cancer risk and epigenome-wide methylation in DNA from peripheral blood. Nested case-control study within the prospective Melbourne Collaborative Cohort Study. DNA was extracted from before-diagnosis blood samples (420 incident cases and matched controls). Methylation was measured with the Illumina Infinium Human Methylation 450 BeadChip array. Odds ratio (OR) for epigenome-wide methylation, quantified as the mean beta values across the CpGs, in relation to breast cancer risk were estimated using conditional logistic regression. Overall, the OR for breast cancer was 0.42 (95% CI 0.20-0.90) for the top versus bottom quartile of epigenome-wide DNA methylation and the OR for a one standard deviation increment was 0.69 (95% CI 0.50-0.95; test for linear trend, p = 0.02). Epigenome-wide DNA methylation of CpGs within functional promoters was associated with an increased risk, whereas epigenome-wide DNA methylation of genomic regions outside promoters was associated with decreased risk (test for heterogeneity, p = 0.0002). The increased risk associated with epigenome-wide DNA methylation in functional promoters did not vary by time between blood collection and diagnosis, whereas the inverse association with epigenome-wide DNA methylation outside functional promoters was strongest when the interval from blood collection to diagnosis was less than 5 years and weakest for the longest interval. Epigenome-wide methylation in DNA extracted from peripheral blood collected before diagnosis may have potential utility as markers of breast cancer risk and for early detection.
Published: 2014
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29. Fine-Scale Mapping of the FGFR2 Breast Cancer Risk Locus: Putative Functional Variants Differentially Bind FOXA1 and E2F1

Author: Per Hall, Hui Cai, Roger L. Milne, Douglas F. Easton, Anja Rudolph, José Ignacio Arias, Vessela N. Kristensen, Julia A. Knight, Lisa B. Signorello, Petra Seibold, Jonathan Tyrer, Arto Mannermaa, Alan Ashworth, Andreas Schneeweiss, Sandra Deming-Halverson, Katarzyna Durda, Kimael Eriksson, Thilo Dörk, Isabel dos Santos Silva, Alfons Meindl, Laura Baglietto, Fredrick R. Schumacher, Peter Devilee, Qiuyin Cai, Janet E. Olson, Keith Humphreys, Annegien Broeks, Soo Hwang Teo, Michael P. Lux, Sze Yee Phuah, Federick Marme, Pascal Guénel, Hidemi Ito, Irene L. Andrulis, Natalia Bogdanova, Christoph Engel, Juliet D. French, Nina Ditsch, Xianshu Wang, Susan L. Slager, Bernardo Bonanni, Hermann Brenner, Nick Orr, Marie Rose Christiaens, Martine Dumont, Martin O'Reilly, Annika Lindblom, Catriona McLean, Ans M.W. van den Ouweland, Marjanka K. Schmidt, Sara Margolin, Kerstin B. Meyer, Martha J. Shrubsole, Malcolm W.R. Reed, Hans Ulrich Ulmer, Georgia Chenevix-Trench, Kyriaki Michailidou, Brian E. Henderson, Nicola Miller, Sandrine Tchatchou, Stig E. Bojesen, Pornthep Siriwanarangsan, Joe Dennis, Jaana M. Hartikainen, Matthias W. Beckmann, Fergus J. Couch, David Van Den Berg, Celine M. Vachon, Pierre Laurent-Puig, Montserrat Garcia-Closas, Ian Tomlinson, Thomas Brüning, Maya Ghoussaini, Mikael Hartman, Kristiina Aittomäki, Thérèse Truong, Katarzyna Jaworska, Yon Ko, Yu Tang Gao, Paolo Peterlongo, Stacey L. Edwards, Saskia Carlebur, Hartef Darabi, Pei Ei Wu, Ute Hamann, M. Pilar Zamora, Taru A. Muranen, Jirong Long, Stephen J. Chanock, William Blot, Sonja Helbig, Heiko Müller, Christina Clarke Dur, Ji Yeob Choi, Melissa C. Southey, Olivia Fletcher, Ming-Feng Hou, Hiroji Iwata, Nichola Johnson, Wei Zheng, Robert Winqvist, Diether Lambrechts, Javier Benitez, Chen-Yang Shen, Suleeporn Sangrajrang, Chia-Ni Hsiung, James McKay, Kristen S. Purrington, Cheng Har Yip, Ann Smeets, Valerie Gaborieau, Keitaro Matsuo, Anthony J. Swerdlow, Anne Lise Børresen-Dale, Anna Jakubowska, Dong Young Noh, Paul D.P. Pharoah, Ines de Santiago, Hiltrud Brauch, Vesa Kataja, Yasushi Yatabe, Anna H. Wu, Grethe I. Grenaker Alnæs, Jonine D. Figueroa, Christopher A. Haiman, Florence Menegaux, Hoda Anton-Culver, Paul Brennan, Veli-Matti Kosma, Bruce A.J. Ponder, Dieter Flesch-Janys, Thomas Rüdiger, Shaik Ahmad Buhari, Katri Pylkäs, Gord Glendon, Rita K. Schmutzler, Julian Peto, Chiu-Chen Tseng, Sune F. Nielsen, Mark S. Goldberg, Angela Cox, Carolien H.M. van Deurzen, Artitaya Lophatananon, Radhika Prathalingham, Børge G. Nordestgaard, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Florentia Fostira, Wei-Yen Lim, Barbara Burwinkel, Jenny Chang-Claude, Michael J. Kerin, Maartje J. Hooning, Kamila Czene, Asta Försti, Loic Le Marchand, Gianluca Severi, Volker Arndt, John L. Hopper, Jan Lubinski, Jacques Simard, Frans B. L. Hogervorst, Alison M. Dunning, Kenneth Muir, Saila Kauppila, Laura J. van't Veer, John W.M. Martens, Helen Tsimiklis, Loris Bernard, Heli Nevanlinna, Jolanta Lissowska, Robert Pilarski, Qin Wang, Paolo Radice, Robert A.E.M. Tollenaar, Jianjun Liu, Graham G. Giles, Henrik Flyger, Arif B. Ekici, Xiao-Ou Shu, Manjeet K. Bolla, Carl Blomqvist, Daehee Kang, Argyrios Ziogas, Bernard Thienpont, Patricia Harrington, Sue K. Park, Christa Stegmaier, Sarah Stewart-Brown, Elinor J. Sawyer, Miao Hui, Susan L. Neuhausen, Daniel O. Stram, Christof Sohn, Minouk J. Schoemaker, Jingmei Li, Carmel Apicella, Caroline M. Seynaeve, Clinical Genetics, Medical Oncology, Pathology, and Cardiothoracic Surgery
Subjects: Fibroblast Growth Factor, african-american, Genome-wide association study, Medical and Health Sciences, Chromosome conformation capture, 0302 clinical medicine, 2.1 Biological and endogenous factors, Genetics(clinical), Aetiology, Promoter Regions, Genetic, Genetics (clinical), Cancer, African Continental Ancestry Group, Genetics & Heredity, Genetics, 0303 health sciences, Tumor, Chromosome Mapping, Biological Sciences, 3. Good health, Chromatin, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, kConFab Investigators, Female, RNA Interference, women, GENICA Network, transcription, reveals, Type 2, Alleles, Asian Continental Ancestry Group, Binding Sites, Breast Neoplasms, Case-Control Studies, Cell Line, Tumor, Chromatin Immunoprecipitation, E2F1 Transcription Factor, European Continental Ancestry Group, Genetic Association Studies, Haplotypes, Hepatocyte Nuclear Factor 3-alpha, Humans, Position-Specific Scoring Matrices, Protein Binding, Receptor, Fibroblast Growth Factor, Type 2, Genetic Loci, Receptor, Australian Ovarian Cancer Study Group, Black People, Single-nucleotide polymorphism, Locus (genetics), Biology, determinant, White People, Article, Cell Line, estrogen-receptor binding, Promoter Regions, 03 medical and health sciences, Genetic, SDG 3 - Good Health and Well-being, Asian People, Breast Cancer, expression, ddc:610, Allele, 030304 developmental biology, Neoplastic, Prevention, Human Genome, Molecular biology, susceptibility loci, Gene Expression Regulation, genome-wide association, chromatin, Hypersensitive site, Chromatin immunoprecipitation
Abstract: The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ERα to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease. © 2013 The American Society of Human Genetics.
Published: 2013
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30. 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
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31. Associations of Breast Cancer Risk Factors With Tumor Subtypes: A Pooled Analysis From the Breast Cancer Association Consortium Studies

Author: Gillian S. Dite, Brian E. Henderson, U Hamann, Rulla M. Tamimi, Agnes Jager, Laurence N. Kolonel, J Heinz, Hans Wildiers, Celine M. Vachon, Päivi Heikkilä, Chen-Yang Shen, Laura J. Van 'T Veer, Pasi Hirvikoski, Suleeporn Sangrajrang, James McKay, Päivi Auvinen, Michael Bremer, Ann Smeets, Kamila Czene, William J. Tapper, Peter Hillemanns, Fergus J. Couch, John L. Hopper, Douglas F. Easton, Jose Ignacio Arias Perez, Roger L. Milne, Helen Tsimiklis, Carmel Apicella, Antoinette Hollestelle, Zachary S. Fredericksen, Argyrios Ziogas, Helen Cramp, Melissa C. Southey, Malcolm W.R. Reed, Tjoung Won Park-Simon, Janet E. Olson, Primitiva Menéndez Rodríguez, Robert Winqvist, Fabrice Odefrey, Bohdan Górski, Caroline Seynaeve, Matthew L. Kosel, Valerie Gaborieau, Mia M. Gaudet, Diether Lambrechts, Anna Jakubowska, Paul D.P. Pharoah, Fleur Hammet, Amanda B. Spurdle, Stig E. Bojesen, Thilo Dörk, Victoria Cafourek, Julia A. Knight, Frances P O'Malley, Daniel Connley, Letitia D. Smith, David L. Wachter, Flora E. van Leeuwen, David Dynnes Ørsted, Helene Holland, Sabapathy P. Balasubramanian, Aysun Ay, Tuomas Heikkinen, Jaana M. Kauppinen, Diljit Kaur-Knudsen, Børge G. Nordestgaard, Gord Glendon, Paul Brennan, Jacek Gronwald, Mervi Grip, Elinor J. Sawyer, Kristy Driver, Jan Lubinski, Hoda Anton-Culver, Louise A. Brinton, Veli-Matti Kosma, Mieke Kriege, P. E.A. Huijts, Irene L. Andrulis, P. Zamora, S. Chanock, Pei Ei Wu, Tomasz Byrski, Arja Jukkola-Vuorinen, Peter A. Fasching, Tomasz Huzarski, Hatef Darabi, Andreas Meyer, Raem Tollenaar, Fiona M. Blows, Ian Tomlinson, Xiaohong R. Yang, Dallas R. English, Diana Eccles, Ans M.W. van den Ouweland, Johann H. Karstens, Montserrat Garcia-Closas, Alina Vrieling, Graham G. Giles, Michael J. Kerin, Show Lin Yang, Nicola Miller, Sue Gerty, Thomas Brüning, Christopher A. Haiman, Kari Mononen, Loic Le Marchand, Jyh Cherng Yu, Anna Marie Mulligan, Jenny Chang-Claude, Christian R. Loehberg, Matthias W. Beckmann, Madeleine M.A. Tilanus-Linthorst, Angela Cox, Maartje J. Hooning, Susan E. Hankinson, Gianluca Severi, Angela M. Jones, Heli Nevanlinna, Caroline Weltens, Jolanta Lissowska, Hiltrud Brauch, Giu Cheng Hsu, Sebastian M. Jud, Per Hall, Hans Fischer, Arto Mannermaa, Christina Justenhoven, Laura Baglietto, Katri Pylkäs, Kristiina Aittomäki, Sara Margolin, T. Vandorpe, M. Barile, Ylermi Soini, Beate Pesch, Ellen L. Goode, Nayana Weerasooriya, Peter Devilee, Carl Blomqvist, Margriet Collée, Vesa Kataja, Arndt Hartmann, Manjeet K. Humphreys, Siranoush Manoukian, Annika Lindblom, Marjanka K. Schmidt, Yon Ko, Patrick Neven, Chia-Ni Hsiung, Xianshu Wang, Keith Humphreys, Dieter Flesch-Janys, Niall M. McInerney, Javier Benítez, Esther M. John, Jianjun Liu, Peter Sinn, Reijo Sironen, Annegien Broeks, Rebecca Hein, Shou Tung Chen, Paolo Radice, Simon S. Cross, Mark E. Sherman, Robert Paridaens, Shan Wang-Gohrke, Sebastian B. Weihbrecht, Jonine D. Figueroa, Catriona McLean, Georgia Chenevix-Trench, David J. Hunter, Henrik Flyger, Beata Peplonska, VU University medical center, EMGO - Quality of care, Virology, Medical Oncology, Clinical Genetics, Surgery, and University of Groningen
Subjects: Oncology, Cancer Research, Receptor, ErbB-2, Estrogen receptor, Body Mass Index, ErbB-2, 0302 clinical medicine, Risk Factors, Receptors, Odds Ratio, EPITHELIAL OVARIAN-CANCER, Progesterone, REPAIR GENES, 2. Zero hunger, 0303 health sciences, education.field_of_study, Tumor, Medicine (all), Age Factors, SINGLE-NUCLEOTIDE POLYMORPHISMS, Articles, 3. Good health, ErbB Receptors, Parity, ESTROGEN, Receptors, Estrogen, POSTMENOPAUSAL WOMEN, 030220 oncology & carcinogenesis, Female, Breast disease, Receptors, Progesterone, Receptor, Receptor, erbB-2, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Oncology and Carcinogenesis, Population, Breast Neoplasms, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Biomarkers, Tumor, medicine, Humans, Oncology & Carcinogenesis, Obesity, Risk factor, education, 030304 developmental biology, Menarche, HORMONE-RECEPTOR, DIFFERENT HISTOPATHOLOGIC TYPES, Epidermal Growth Factor, business.industry, Parturition, Case-control study, Case-Control Studies, Keratin-5, Logistic Models, Receptor, Epidermal Growth Factor, Cancer, Odds ratio, BASAL-LIKE SUBTYPE, medicine.disease, Endocrinology, PROGESTERONE-RECEPTOR STATUS, business, Biomarkers
Abstract: BACKGROUND: Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. METHODS: We pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided. RESULTS: In case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ≥ 30 kg/m(2)) in younger women (≤50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors. CONCLUSIONS: This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.
Published: 2010
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32. Breast Cancer Risk Prediction Using Clinical Models and 77 Independent Risk-Associated SNPs for Women Aged Under 50 Years: Australian Breast Cancer Family Registry

Author: Gillian S. Dite, Melissa C. Southey, Robert J. MacInnis, Carmel Apicella, Adrian Bickerstaffe, Helen Tsimiklis, Graham G. Giles, James G. Dowty, Roger L. Milne, Kelly-Anne Phillips, Richard Allman, John L. Hopper, and Mary Beth Terry
Subjects: 0301 basic medicine, Oncology, Adult, medicine.medical_specialty, Epidemiology, Population, Breast Neoplasms, Logistic regression, Bioinformatics, Polymorphism, Single Nucleotide, Risk Assessment, Article, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Breast cancer, Risk Factors, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Registries, education, education.field_of_study, Framingham Risk Score, Receiver operating characteristic, business.industry, Case-control study, Australia, Cancer, Middle Aged, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, Case-Control Studies, Female, business, Risk assessment
Abstract: Background: The extent to which clinical breast cancer risk prediction models can be improved by including information on known susceptibility SNPs is not known. Methods: Using 750 cases and 405 controls from the population-based Australian Breast Cancer Family Registry who were younger than 50 years at diagnosis and recruitment, respectively, Caucasian and not BRCA1 or BRCA2 mutation carriers, we derived absolute 5-year risks of breast cancer using the BOADICEA, BRCAPRO, BCRAT, and IBIS risk prediction models and combined these with a risk score based on 77 independent risk-associated SNPs. We used logistic regression to estimate the OR per adjusted SD for log-transformed age-adjusted 5-year risks. Discrimination was assessed by the area under the receiver operating characteristic curve (AUC). Calibration was assessed using the Hosmer–Lemeshow goodness-of-fit test. We also constructed reclassification tables and calculated the net reclassification improvement. Results: The ORs for BOADICEA, BRCAPRO, BCRAT, and IBIS were 1.80, 1.75, 1.67, and 1.30, respectively. When combined with the SNP-based score, the corresponding ORs were 1.96, 1.89, 1.80, and 1.52. The corresponding AUCs were 0.66, 0.65, 0.64, and 0.57 for the risk prediction models, and 0.70, 0.69, 0.66, and 0.63 when combined with the SNP-based score. Conclusions: By combining a 77 SNP-based score with clinical models, the AUC for predicting breast cancer before age 50 years improved by >20%. Impact: Our estimates of the increased performance of clinical risk prediction models from including genetic information could be used to inform targeted screening and prevention. Cancer Epidemiol Biomarkers Prev; 25(2); 359–65. ©2015 AACR.
Published: 2015

33. Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization

Author: S. Lindstrom, Javier Benitez, Natalia Bogdanova, Christine B. Ambrosone, Judith S. Brand, Joe Dennis, Hoda Anton-Culver, Carl Blomqvist, Katarzyna Durda, Loic Le Marchand, Hiltrud Brauch, Aida Karina Dieffenbach, Veli-Matti Kosma, Heli Nevanlinna, Caroline Seynaeve, Drakoulis Yannoukakos, Gord Glendon, Stephen Burgess, Kyriaki Michailidou, Jolanta Lissowska, Thilo Dörk, Paolo Peterlongo, Helen Tsimiklis, J Lubinski, Melissa C. Southey, Robert Winqvist, Kamila Czene, Sune F. Nielsen, Anja Rudolph, Vessela N. Kristensen, Alison M. Dunning, Catherine S. Healey, Diether Lambrechts, Christi J. van Asperen, M. Rosario Alonso, C. Stegmaier, Giuseppe Floris, Per Hall, Jaana M. Hartikainen, Chun Li, Malcolm W.R. Reed, Nuria Álvarez, Anna Jakubowska, Paul D.P. Pharoah, Sara Margolin, John L. Hopper, Barbara Perkins, Francois Bacot, Michael Jones, Jacques Simard, Katarzyna Jaworska-Bieniek, Fredrick R. Schumacher, Angela Cox, Jonine D. Figueroa, Julia A. Knight, Petra Seibold, Alan Ashworth, Arja Jukkola-Vuorinen, Arif B. Ekici, Mervi Grip, Rongxi Yang, Esther M. John, Kathleen E. Malone, Vesa Kataja, Qin Wang, Fergus J. Couch, Keith Humphreys, Katja van den Hurk, Michael J. Kerin, Anna González-Neira, Jenny Chang-Claude, Daniel Vincent, Wei Zheng, Ian Tomlinson, Madeleine M. A. Tilanus-Linthorst, Ute Hamann, Amanda E. Toland, Xiao-Ou Shu, Dieter Flesch-Janys, Volker Arndt, Graham G. Giles, Rita K. Schmutzler, Julian Peto, Craig Luccarini, Børge G. Nordestgaard, Grethe I. Grenaker Alnæs, Alice S. Whittemore, Olivia Fletcher, Guillermo Pita, Matti A. Rookus, Barbara Burwinkel, Lothar Haeberle, Hermann Brenner, John W. M. Martens, Mitul Shah, Marilie D. Gammon, Patrick Neven, Emilie Cordina-Duverger, Jose Ignacio Arias Perez, Ben Zhang, Martine Dumont, Mel Maranian, Annika Lindblom, Habibul Ahsan, Susan L. Neuhausen, Mikael Eriksson, Jingmei Li, Carmel Apicella, Frederik Marmé, Peter Kraft, Hatef Darabi, Ulrike Peters, Hans Wildiers, Arto Mannermaa, J. Margriet Collée, Pascal Guénel, Peter Devilee, M.J. Hooning, Daniel C. Tessier, Shahana Ahmed, Paolo Radice, Montserrat Garcia-Closas, Elinor J. Sawyer, Louise A. Brinton, Susan L. Slager, Bernardo Bonanni, Peter A. Fasching, Simon S. Cross, Thérèse Truong, Matthias W. Beckmann, Catriona McLean, Douglas F. Easton, Georgia Chenevix-Trench, David J. Hunter, Kristiina Aittomäki, Janet E. Olson, Henrik Flyger, Chenjie Zeng, Nick Orr, Siranoush Manoukian, Antonenkova Nn, Stig E. Bojesen, Wan-Qing Wen, Jirong Long, Nicola Miller, Brandon L. Pierce, Ryan J. Delahanty, Anthony J. Swerdlow, Brian E. Henderson, Harald Surowy, Yon-Dschun Ko, Celine M. Vachon, Daniel Herrero, Christopher A. Haiman, Sandrine Tchatchou, Florence Menegaux, Katri Pylkäs, Taru A. Muranen, Roger L. Milne, Thomas Brüning, Marjanka K. Schmidt, Manjeet K. Bolla, M. Pilar Zamora, Irene L. Andrulis, Caroline Baynes, Emily Hallberg, D. Seminara, Isabel dos-Santos-Silva, Diana Torres, Wim L. A. M. de Kort, Nichola Johnson, Public and occupational health, Clinical Genetics, Virology, Medical Oncology, Surgery, and Landsteiner Laboratory
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Pathology, coronary-artery-disease, prospective cohort, Genome-wide association study, Breast Neoplasms, Article, different anatomic sites, Breast cancer, SDG 3 - Good Health and Well-being, Risk Factors, Internal medicine, common variants, Mendelian randomization, Odds Ratio, Medicine, Humans, Prospective Studies, Risk factor, Prospective cohort study, Evidence-Based Medicine, business.industry, body-fat distribution, Mendelian Randomization Analysis, multiple genetic-variants, Odds ratio, medicine.disease, susceptibility loci, Body Height, interleukin-6 receptor, adult human height, Relative risk, genome-wide association, Female, business
Abstract: Background: Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear. Methods: We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5 216 302 women, including 113 178 events. In a consortium with individual-level data from 46 325 case patients and 42 482 control subjects, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16 003 case patients and 41 335 control subjects. Results: The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10 cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10 cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5 × 10-8. Conclusions: Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.
Published: 2015
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34. Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer

Author: Melissa C. Southey, Fredrick R. Schumacher, Robert Winqvist, Simon S. Cross, Katarzyna Durda, Anna Jakubowska, Paul D.P. Pharoah, Judith S. Brand, Christi J. van Asperen, Javier Benitez, Isabel dos-Santos-Silva, Douglas F. Easton, Roger L. Milne, Justo Lorenzo Bermejo, Hermann Brenner, Patrick Neven, Frederik Marmé, Marie Sanchez, Peter Bugert, Maria Kabisch, Anja Rudolph, Arto Mannermaa, Thilo Dörk, Diether Lambrechts, Anna González-Neira, Hoda Anton-Culver, Thomas Dünnebier, Matthias Ruebner, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Veli-Matti Kosma, Christopher A. Haiman, Dieter Flesch-Janys, Martha J. Shrubsole, Florence Menegaux, Catriona McLean, Olivia Fletcher, Kamila Czene, Mark S. Goldberg, Per Hall, Jacques Simard, Keith Humphreys, Qin Wang, Georgia Chenevix-Trench, Katarzyna Jaworska-Bieniek, Jan Lubinski, Loic Le Marchand, Katri Pylkäs, Barbara Perkins, Kristen S. Purrington, Daniel C. Tessier, Paolo Radice, Craig Luccarini, Sune F. Nielsen, Paolo Peterlongo, Nicola Miller, Jonine D. Figueroa, Julia A. Knight, Petra Seibold, Alan Ashworth, John L. Hopper, Annegien Broeks, Kristiina Aittomäki, Mieke Kriege, Sandrine Tchatchou, Frans B. L. Hogervorst, Jenny Chang-Claude, Robert A.E.M. Tollenaar, Angela Cox, Maartje J. Hooning, Brian E. Henderson, Seth W. Slettedahl, Montserrat Garcia-Closas, Thomas Brüning, Malcolm W.R. Reed, Francois Bacot, Alison M. Dunning, kConFab Investigators, Julian Peto, Børge G. Nordestgaard, Linetta B. Koppert, Volker Arndt, Rongxi Yang, Celine M. Vachon, Peter Devilee, Qiuyin Cai, Caroline Weltens, Hiltrud Brauch, Heli Nevanlinna, Sara Margolin, Mitul Shah, Matthias W. Beckmann, Stig E. Bojesen, Giulietta Scuvera, Kyriaki Michailidou, Jolanta Lissowska, Marjanka K. Schmidt, Fergus J. Couch, Barbara Burwinkel, Ute Hamann, Jaana M. Hartikainen, Janet E. Olson, Natalia Bogdanova, Irene L. Andrulis, M. Pilar Zamora, Caroline Baynes, Gord Glendon, Wei Zheng, Taru A. Muranen, Drakoulis Yannoukakos, Caroline Seynaeve, Aida Karina Dieffenbach, Stefano Fortuzzi, Mel Maranian, Arif B. Ekici, Nick Orr, Annika Lindblom, Nichola Johnson, Arja Jukkola-Vuorinen, Anthony J. Swerdlow, Peter A. Fasching, Sten Cornelissen, Martine Dumont, Diana Torres, Helen Tsimiklis, Yon-Dschun Ko, Vesa Kataja, Shibo Ying, Jingmei Li, Carmel Apicella, Vessela N. Kristensen, Hatef Darabi, Christa Stegmaier, Stéphanie Peeters, Michael J. Kerin, Graham G. Giles, Elinor J. Sawyer, Minouk J. Schoemaker, Manjeet K. Bolla, Carl Blomqvist, Xianshu Wang, Joe Dennis, Stephen J. Chanock, Mervi Grip, Jose Ignacio Arias Perez, Mikael Eriksson, Daniel Vincent, Antoinette Hollestelle, Pascal Guénel, Shahana Ahmed, Henrik Flyger, Clinical Genetics, Medical Oncology, and Surgery
Subjects: Risk, Cancer Research, Candidate gene, kinase, Chromosomal Proteins, Non-Histone, Survivin, European Continental Ancestry Group, Estrogen receptor, cytokinesis, Original Manuscript, Single-nucleotide polymorphism, Genome-wide association study, Breast Neoplasms, Cell Cycle Proteins, Biology, metaphase, Polymorphism, Single Nucleotide, White People, Inhibitor of Apoptosis Proteins, Breast cancer, SDG 3 - Good Health and Well-being, Medizinische Fakultät, cleavage furrow, Genotype, medicine, Aurora Kinase B, Humans, Genetic Predisposition to Disease, ddc:610, Allele, skin and connective tissue diseases, 3' Untranslated Regions, mitosis, Genetics, INCENP, aurora-b, General Medicine, medicine.disease, segregation, mammaglobin, Receptors, Estrogen, midbody, Case-Control Studies, Female, Genome-Wide Association Study
Abstract: The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixedeffects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92-0.98, P = 0.007 and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83-0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3' untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00-1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02-1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04-1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated. Â© The Author 2015.
Published: 2015

35. Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

Author: Suleeporn Sangrajrang, James McKay, Jirong Long, Gord Glendon, Qi Guo, Malcolm W.R. Reed, Yon Dschun Koto, Sara Margolin, Francois Bacot, Julian Peto, Shaik Ahmad Buhari, Fredrick R. Schumacher, Jose Ignacio Arias Perez, Børge G. Nordestgaard, Kamila Czene, Barbara Burwinkel, Mikael Eriksson, Lorna Gibson, Mitul Shah, Matthias W. Beckmann, Shahana Ahmed, Anthony J. Swerdlow, Frederik Marmé, Pascal Guénel, Hidemi Ito, Mark S. Goldberg, Laura J. van't Veer, John W.M. Martens, Wei Zheng, John L. Hopper, Susanne Kaufmann, Carlos Caldas, Jonathan Beesley, Paolo Peterlongo, Ji Yeob Choi, Daniel O. Stram, Sarah Stewart-Brown, Elinor J. Sawyer, Craig Luccarini, Anja Rudolph, Qin Wang, Javier Benitez, Marie Sanchez, Daniel Herrero, Catherine S. Healey, Arto Mannermaa, Daniel C. Tessier, Paolo Radice, David Van Den Berg, Jacques Simard, Hoda Anton-Culver, Stephen J. Chanock, Christopher A. Haiman, Ines de Santiago, Minouk J. Schoemaker, Irene L. Andrulis, Veli-Matti Kosma, Isabel dos-Santos-Silva, Caroline Baynes, Douglas F. Easton, Stacey L. Edwards, Florence Menegaux, Hatef Darabi, Kyriaki Michailidou, Anna H. Wu, Carolien H.M. van Deurzen, Annegien Broeks, Paul Brennan, Sonja Helbig, Melissa C. Southey, Daniel Klevebring, Loic Le Marchand, Katri Pylkäs, J. Margriet Collée, Ed Dicks, Robert A.E.M. Tollenaar, Henrik Flyger, Jenny Chang-Claude, Annika Lindblom, Christine B. Ambrosone, Lothar Haeberle, Janet E. Olson, Sune F. Nielsen, Robert Winqvist, M. Pilar Zamora, Emily Hallberg, Vessela N. Kristensen, Hermann Brenner, Diana Torres, Valerie Gaborieau, Keitaro Matsuo, Yu-Tang Gao, Yik Ying Teo, Anna Jakubowska, Paul D.P. Pharoah, Patrick Neven, Vesa Kataja, Fergus J. Couch, Robert Luben, Ute Hamann, Katarzyna Jaworska-Bieniek, Dylan M. Glubb, Nick Orr, Christi J. van Asperen, Sara Volorio, Tien Yin Wong, Keith Humphreys, Jianjun Liu, Helen Tsimiklis, Thilo Dörk, Jaana M. Hartikainen, Guillermo Pita, Daniel Vincent, Roger L. Milne, M. Rosario Alonso, Nuria Álvarez, Chiu-Chen Tseng, Daehee Kang, Martine Dumont, Richard Cowper-Sal-lari, Mathieu Lupien, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Xiao-Ou Shu, Brian E. Henderson, Miroslav Kapuscinski, Hui Miao, Angela Cox, Caroline Seynaeve, Stig E. Bojesen, Jason S. Carroll, Nicola Miller, Marjanka K. Schmidt, Taru A. Muranen, Celine M. Vachon, Manjeet K. Bolla, Hans Wildiers, Carl Blomqvist, Maartje J. Hooning, Sandrine Tchatchou, Maya Ghoussaini, Cheng Har Yip, Artitaya Lophatananon, Graham G. Giles, Penny Webb, Yasushi Yatabe, Aida Karina Dieffenbach, Mikael Hartman, Volker Arndt, Simon S. Cross, Per Hall, Soo Hwang Teo, Arif B. Ekici, Joe Dennis, Heli Nevanlinna, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Jonine D. Figueroa, Julia A. Knight, Petra Seibold, Jolanta Lissowska, Kinjal Desai, Alan Ashworth, Jan Lubinski, Primitiva Menéndez, Pei Ei Wu, Natalia Bogdanova, Kristine M. Hillman, Juliet D. French, Andreas Schneeweiss, Drakoulis Yannoukakos, Montserrat Garcia-Closas, Catriona McLean, Georgia Chenevix-Trench, Pornthep Siriwanarangsan, Thomas Brüning, Kristiina Aittomäki, Silje Nord, Jyh Cherng Yu, Hiltrud Brauch, Peter Devilee, Anne Lise Børresen-Dale, Susan L. Slager, Melissa A. Brown, Qiuyin Cai, Hiroji Iwata, Diether Lambrechts, Bernardo Bonanni, Katarzyna Durda, Emiel J. Th. Rutgers, Grethe I. Grenaker Alnæs, Anna de Fazio, Siddhartha Kar, Mel Maranian, Susan L. Neuhausen, Judith E. Brown, Christof Sohn, Sue K. Park, Christa Stegmaier, Shou Tung Chen, Dong-Young Noh, Bernard Thienpont, Alison M. Dunning, Kenneth Muir, Daphne S.C. Lee, Michael J. Kerin, Dieter Flesch-Janys, Jingmei Li, Chen-Yang Shen, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Pathology, Cardiothoracic Surgery, International Institute of Social Studies, Ghoussaini, Maya [0000-0002-2415-2143], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Dicks, Ed [0000-0002-0617-0401], Luben, Robert [0000-0002-5088-6343], Carroll, Jason [0000-0003-3643-0080], Caldas, Carlos [0000-0003-3547-1489], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Dunning, Alison [0000-0001-6651-7166], and Apollo - University of Cambridge Repository
Subjects: General Physics and Astronomy, Genome-wide association study, in-vivo, Genotype, phase, cyclin d1 expression, Promoter Regions, Genetic, CYCLIN D1 EXPRESSION, IN-VIVO, Genetics, Multidisciplinary, FACTOR-BINDING PROTEIN-5, foxa1, ASSOCIATION, Chromatin, 3. Good health, Multidisciplinary Sciences, Chromosomes, Human, Pair 2, functional variants, MCF-7 Cells, Science & Technology - Other Topics, GROWTH, Female, Hepatocyte Nuclear Factor 3-alpha, growth, PHASE, Breast Neoplasms, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Breast cancer, SDG 3 - Good Health and Well-being, Cell Line, Tumor, medicine, Humans, SNP, Genetic Predisposition to Disease, RNA, Messenger, FUNCTIONAL VARIANTS, Gene, Science & Technology, association, Correction, General Chemistry, medicine.disease, CELLS, factor-binding protein-5, cells, FOXA1, Insulin-Like Growth Factor Binding Protein 5
Abstract: GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology. ispartof: Nature communications vol:5 pages:4999- ispartof: location:England status: published
Published: 2014

36. Rare mutations in RINT1 predispose carriers to breast and Lynch syndrome-spectrum cancers

Author: Mary B. Daly, Fabrice Odefrey, John L. Hopper, Andrew Lonie, Sean V. Tavtigian, Erin L. Young, Jun Li, Igor V. Makunin, Kayoko Tao, Hao Hu, Fleur Hammet, Graham G. Giles, Terrell C Roane, Jonathan Ellis, Russell Bell, Irene L. Andrulis, Nivonirina Robinot, Melissa C. Southey, Catherine Voegele, Carrie Snyder, Louise B. Thingholm, David E. Goldgar, Mary Beth Terry, Esther M. John, Daniel J. Park, Tu Nguyen-Dumont, Zhi Ling Teo, Shankaracharya, Henry T. Lynch, Bing Jian Feng, Saundra S. Buys, Fabienne Lesueur, Peter Devilee, Florence Le Calvez-Kelm, Helen Tsimiklis, Bernard J. Pope, and Chad D. Huff
Subjects: Oncology, Male, medicine.medical_specialty, Population, Breast Neoplasms, Cell Cycle Proteins, Biology, Bioinformatics, Breast cancer, Internal medicine, medicine, Humans, Exome, Genetic Predisposition to Disease, education, Exome sequencing, Genetic testing, education.field_of_study, medicine.diagnostic_test, Cancer, Family aggregation, Genetic Variation, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, Pedigree, Case-Control Studies, Mutation, Female
Abstract: Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome-sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C>T (p.Q115X), c.1132_1134del (p.M378del), and c.1207G>T (p.D403Y). On the basis of this finding, a population-based case–control mutation-screening study was conducted that identified 29 carriers of rare (minor allele frequency < 0.5%), likely pathogenic variants: 23 in 1,313 early-onset breast cancer cases and six in 1,123 frequency-matched controls [OR, 3.24; 95% confidence interval (CI), 1.29–8.17; P = 0.013]. RINT1 mutation screening of probands from 798 multiple-case breast cancer families identified four additional carriers of rare genetic variants. Analysis of the incidence of first primary cancers in families of women carrying RINT1 mutations estimated that carriers were at increased risk of Lynch syndrome–spectrum cancers [standardized incidence ratio (SIR), 3.35; 95% CI, 1.7–6.0; P = 0.005], particularly for relatives diagnosed with cancer under the age of 60 years (SIR, 10.9; 95% CI, 4.7–21; P = 0.0003). Significance: The work described in this study adds RINT1 to the growing list of genes in which rare sequence variants are associated with intermediate levels of breast cancer risk. Given that RINT1 is also associated with a spectrum of cancers with mismatch repair defects, these findings have clinical applications and raise interesting biological questions. Cancer Discov; 4(7); 804–15. ©2014 AACR. See related commentary by Ngeow and Eng, p. 762 This article is highlighted in the In This Issue feature, p. 745
Published: 2014

37. Cross-platform compatibility of Hi-Plex, a streamlined approach for targeted massively parallel sequencing

Author: Helen Tsimiklis, Bernard J. Pope, Maryam Mahmoodi, Melissa C. Southey, Fleur Hammet, Daniel J. Park, and Tu Nguyen-Dumont
Subjects: Genetics, Massive parallel sequencing, Time Factors, fungi, Biophysics, 2 base encoding, High-Throughput Nucleotide Sequencing, Cell Biology, Computational biology, Ion semiconductor sequencing, Sequence Analysis, DNA, Biology, Molecular diagnostics, Biochemistry, Polymerase Chain Reaction, Article, Single cell sequencing, Cross-platform, Genomic library, Molecular Biology, ABI Solid Sequencing, Gene Library
Abstract: Although per-base sequencing costs have decreased during recent years, library preparation for targeted massively parallel sequencing remains constrained by high reagent cost, limited design flexibility, and protocol complexity. To address these limitations, we previously developed Hi-Plex, a polymerase chain reaction (PCR) massively parallel sequencing strategy for screening panels of genomic target regions. Here, we demonstrate that Hi-Plex applied with hybrid adapters can generate a library suitable for sequencing with both the Ion Torrent and the TruSeq chemistries and that adjusting primer concentrations improves coverage uniformity. These results expand Hi-Plex capabilities as an accurate, affordable, flexible, and rapid approach for various genetic screening applications.
Published: 2013

38. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer

Author: Michael Lush, Hans Wildiers, Christopher A. Haiman, Nils Schoof, Per Hall, Beatrice Melin, Hiltrud Brauch, Liisa M. Pelttari, Angela Brooks-Wilson, Laima Tihomirova, Ingo B. Runnebaum, Hui Cai, Kenneth Offit, Michael P. Lux, Robert Edwards, Julia A. Knight, Ignace Vergote, Arto Leminen, Alan Ashworth, Kyriaki Michailidou, Martha J. Shrubsole, Sophie Giraud, Nadeem Siddiqui, Katri Pylkäs, Sune F. Nielsen, Vernon S. Pankratz, Lenka Foretova, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Anna Marie Mulligan, Andreas du Bois, Christi J. van Asperen, Nuria Álvarez, M. Pilar Zamora, Theo A. Mvan Os, Susan J. Ramus, Olivia Fletcher, Usha Menon, Olivier Caron, Dieter Flesch-Janys, Sara H. Olson, Ellen L. Goode, Yael Laitman, Jingmei Li, Lynne R. Wilkens, Carmel Apicella, Brooke L. Fridley, Robert Luben, Mark S. Goldberg, Mary Anne Rossing, Dominique Stoppa-Lyonnet, Jonathan Beesley, Jan Lubinski, Paolo Peterlongo, Phuong L. Mai, Henrik Flyger, Thilo Dörk, Douglas A. Levine, Rob B. van der Luijt, Stig E. Bojesen, Javier Benitez, Natalia Bogdanova, Stephen J. Chanock, Andrew K. Godwin, Sharon E. Johnatty, Helga B. Salvesen, Juliet D. French, Daphne Gschwantler Kaulich, Rod Karevan, Arif B. Ekici, Marc Frenay, Taru A. Muranen, Jirong Long, Catherine S. Healey, Craig Luccarini, Chen-Yang Shen, Lorna Gibson, Pascal Guénel, Hidemi Ito, Nicholas T. Woods, Drakoulis Yannoukakos, Thomas Hansen, Francesca Damiola, Valérie Bonadona, Satoyo Hosono, Marion Piedmonte, Steve Ellis, Suleeporn Sangrajrang, Aleksandra Gentry-Maharaj, James McKay, Olga M. Sinilnikova, Jennifer A. Doherty, Xiao-Ou Shu, Curtis Olswold, Nhu D. Le, Michael J. Kerin, Malcolm C. Pike, Jenny Chang-Claude, Gianluca Severi, Michael Jones, Linda E. Kelemen, Loic Le Marchand, Maureen E. Hoatlin, Fredrick R. Schumacher, Dieter Niederacher, Michael E. Carney, Angela Cox, Attila Teoman, Hannah P. Yang, Graham G. Giles, Jianjun Liu, Xiaoqing Chen, Elisa V. Bandera, Tanja Pejovic, Galina Lurie, Karoline Kuchenbaecker, Mariusz Bidziński, Chanel E. Smart, Maartje J. Hooning, Jose Ignacio Arias Perez, Anne-Marie Gerdes, L. Rogmann, Christoph Engel, Harvey A. Risch, Ignacio Blanco, Isabel dos Santos Silva, Hoda Anton-Culver, Camilla Krakstad, Volker Arndt, Foluso O. Ademuyiwa, Frans B. L. Hogervorst, Stacey L. Edwards, Florian Heitz, Veli-Matti Kosma, Beth Y. Karlan, Robert A. Vierkant, Irene L. Andrulis, Agnieszka Dansonka-Mieszkowska, Hanne Meijers-Heijboer, Alison M. Dunning, Sabapathy P. Balasubramanian, Penny Soucy, Edwin S. Iversen, Heli Nevanlinna, Celeste Leigh Pearce, Melissa C. Southey, Howard C. Shen, Kenneth Muir, Jolanta Lissowska, Clareann H. Bunker, Judy Garber, David Van Den Berg, Yin Ling Woo, Brigitte Bressac-de Paillerets, Rebecca Hein, Norbert Arnold, Saila Kauppila, Lisa Walker, Cezary Cybulski, Estrid Høgdall, Anthony J. Swerdlow, Robert Winqvist, Susanne K. Kjaer, Christa Stegmaier, Kazuo Tajima, Caroline Baynes, Valerie Gaborieau, Keitaro Matsuo, Ed Dicks, Irene Orlow, Torben A Kruse, Rachel Palmieri Weber, David E. Goldgar, Anna Jakubowska, Honglin Song, Antonis C. Antoniou, Paul D.P. Pharoah, Katja K.H. Aben, Lambertus A. Kiemeney, Laurence Faivre, Stefan Nickels, Joellen M. Schildkraut, Yu Tang Gao, Valerie McGuire, Charles L. Shapiro, Sebastian M. Armasu, Katherine L. Nathanson, Marjanka K. Schmidt, Susan L. Neuhausen, Jolanta Kupryjanczyk, Janet E. Olson, Nicolas Wentzensen, Dong Young Noh, Maya Ghoussaini, Ian G. Campbell, Annegien Broeks, Gustavo C. Rodriguez, Rebecca L. Johnston, Shan Wang-Gohrke, Monica Barile, Vesa Kataja, Melanie Maranian, Shahana Ahmed, Christof Sohn, Julie M. Cunningham, Weiva Sieh, Shani Shimon Paluch, Riccardo Dolcetti, John W.M. Martens, Manjeet K. Bolla, Shelley S. Tworoger, Robert S. Brown, Allan Jensen, Hui Miao, Boris Winterhoff, Mari K. Halle, Arndt Hartmann, Loris Bernard, Brian E. Henderson, Els Wauters, Carl Blomqvist, Daniel O. Stram, Karen A. Pooley, Roberta B. Ness, James Paul, Hilda A. Pickett, Wei Zheng, Sandra Deming-Halverson, Soo Hwang Teo, Andrew Lee, Thomas A. Sellers, Philip Iau, D. Gareth Evans, Françis Bacot, Sunil R. Lakhani, Qin Wang, Nick Orr, Celine M. Vachon, Edith Olah, Gong Yang, Svend Aage Engelholm, Martine Dumont, Linda S. Cook, Daniel C. Tessier, Evgeny N. Imyanitov, Paolo Radice, Mikael Hartman, Annika Lindblom, John R. McLaughlin, Radka Platte, Jenny Permuth-Wey, Keun-Young Yoo, Andrew Berchuck, Roger R. Reddel, M. John Kennedy, Toru Nakanishi, Allison F. Vitonis, Melissa C. Larson, Anna H. Wu, Helmut Deissler, Giuseppe Giannini, Barbara Wappenschmidt, Tomasz Byrski, M. Kamran Ikram, Natalia Antonenkova, Banu Arun, Peter Hillemanns, William Blot, Siti Zawiah Omar, Sue Healey, Trevor Cole, Cheng Har Yip, Matthias Dürst, Mark E. Robson, Roger L. Milne, Timothy R. Rebbeck, Jaana M. Hartikainen, Mieke Kriege, C. Ellen van der Schoot, Hansjoerg Plendl, Yasushi Yatabe, Jan C. Oosterwijk, Claus Høgdall, Rob A. E. M. Tollenaar, Jacek Gronwald, Yi Lu, Kate Lawrenson, Michael D. Stutz, Chia-Ni Hsiung, Alvaro N.A. Monteiro, Maren Weischer, Philipp Harter, Nicola Miller, Lisa B. Signorello, Katarzyna Durda, Peter Lichtner, Ritu Salani, Alfons Meindl, Montserrat Garcia-Closas, George Fountzilas, Uffe Birk Jensen, Thomas Brüning, Laura Baglietto, Anne M. van Altena, Kristine M. Hillman, Bernard Peissel, Trinidad Caldés, Rosemarie Davidson, Julian Barwell, Peter Devilee, Jenny Lester, Qiuyin Cai, Heiko Müller, Jyh Cherng Yu, Kerstin Rhiem, Muy Kheng Tea, Sharon A. Savage, Åke Borg, Daniel Vincent, Antoinette Hollestelle, Katarzyna Jaworska, Mat Adenan Noor Azmi, Yon Ko, Kimberly R. Kalli, Debra Frost, Martin Gore, Chiu-Chen Tseng, Georgia Chenevix-Trench, Pornthep Siriwanarangsan, Evelyn Despierre, Fergus J. Couch, Vijayalakshmi Shridhar, Artitaya Lophatananon, Amanda B. Spurdle, Joe Dennis, Ute Hamann, Vessela N. Kristensen, Frederik Marmé, Jonathan Tyrer, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Bruno Buecher, Kristiina Aittomäki, Kirsten B. Moysich, Lesley McGuffog, Mine S. Cicek, Guillermo Pita, Arjen R. Mensenkamp, Agnes Jager, Catherine M. Phelan, Jacques Simard, Ming-Feng Hou, Hiroji Iwata, James M. Flanagan, Elena Fineberg, Susan M. Domchek, Csilla Szabo, Diether Lambrechts, Anja Rudolph, Daehee Kang, Gottfried E. Konecny, Eitan Friedman, Argyrios Ziogas, Arto Mannermaa, Susan Peock, Matti A. Rookus, Christian F. Singer, Claire Mulot, Siranoush Manoukian, Johanna Rantala, Helen Tsimiklis, Gord Glendon, Pierre Laurent-Puig, Barbara Brouwers, Filomena Ficarazzi, Jonine D. Figueroa, Anne-Bine Skytte, Caroline Seynaeve, Christian Sutter, Rita K. Schmutzler, Julian Peto, Jeffrey N. Weitzel, Kathryn L. Terry, Børge G. Nordestgaard, Simon A. Gayther, Barbara Burwinkel, Ira Schwaab, Steven A. Narod, Elisabeth Wik, Ralf Bützow, Marco Montagna, Mark H. Greene, Linde M. Braaf, Janusz Menkiszak, Kamila Czene, Sarah Stewart-Brown, Kees E. P. van Roozendaal, Andreas Schneeweiss, Daniel Barrowdale, Elinor J. Sawyer, Alice S. Whittemore, Marc T. Goodman, Judith E. Brown, Kunle Odunsi, John L. Hopper, Nina Ditsch, Leon F.A.G. Massuger, Hermann Brenner, Joaquin J. Garcia, Xianshu Wang, Susan L. Slager, Aleksandra Tołoczko-Grabarek, Sylvie Mazoyer, Diana Eccles, Yik Ying Teo, Iwona K. Rzepecka, Bernardo Bonanni, Sara Margolin, Daniela Zaffaroni, Yew Ching Teh, Ans M Wvan Den Ouweland, Bent Ejlertsen, Maria Soller, Mitul Shah, Matthias W. Beckmann, Elizabeth M. Poole, J. Margriet Collée, Lorna Rodriguez-Rodriguez, Sandrina Lambrechts, Daniel W. Cramer, Douglas F. Easton, Virginie Caux-Moncoutier, Mads Thomassen, Keith Humphreys, ~, Landsteiner Laboratory, Clinical Haematology, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human Genetics, MUMC+: DA KG Lab Centraal Lab (9), Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Human genetics, CCA - Oncogenesis, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Clinical Genetics, Cardiothoracic Surgery, and Medical Oncology
Subjects: Telomerase, Messenger, Càncer d'ovari, Estrogen receptor, Aetiology, screening and detection [ONCOL 5], 0302 clinical medicine, Breast cancer, Risk Factors, Alternative Splicing, Biomarkers, Tumor, Breast Neoplasms, Case-Control Studies, Chromatin, DNA Methylation, Female, Gene Expression Profiling, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Luciferases, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, Polymorphism, Single Nucleotide, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Telomere, Genetics, BUCCAL CELLS, 0303 health sciences, Tumor, Telòmer, GENETIC-VARIATION, COMMON VARIANTS, Single Nucleotide, tert-clptm1l locus, genome-wide association, genetic-variation, susceptibility loci, buccal cells, fibroblasts, common variants, carcinoma, reverse-transcriptase htert, metaanalysis, Aetiology, screening and detection Immune Regulation [ONCOL 5], 3. Good health, Tumor Markers, Biological, 030220 oncology & carcinogenesis, FIBROBLASTS, SUSCEPTIBILITY LOCI, CARCINOMA, Single-nucleotide polymorphism, Biology, Article, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Ovarian cancer, medicine, Polymorphism, Allele, GENOME-WIDE ASSOCIATION, METAANALYSIS, 030304 developmental biology, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Breast cancer susceptibility, Hereditary cancer and cancer-related syndromes [ONCOL 1], Translational research Genomic disorders and inherited multi-system disorders [ONCOL 3], medicine.disease, Molecular biology, TERT-CLPTM1L LOCUS, Minor allele frequency, RNA, Biomarkers, REVERSE-TRANSCRIPTASE HTERT
Abstract: Journal article TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ~480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10!-7), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10!-8) and BRCA1 mutation carrier (P = 1.1 × 10!-5) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10!-14), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10!-15) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10!-12) and BRCA1 mutation carrier (P = 1.6 × 10!-14) breast and invasive ovarian (P = 1.3 × 10!-11) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant. European Commission Seventh Framework Programme (agreement 223175-HEALTH-F2-2009-223175); Cancer Research UK (C1287/A10118 and C1287/A12014) peer-reviewed
Published: 2013
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39. Expanded genetic analysis of a PALB2 c.3113G>A mutation carrying multiple-case breast cancer family via exome sequencing

Author: Fabrice Odefrey, Daniel J. Park, Andrew Lonie, Helen Tsimiklis, Fleur Hammet, Zhi Ling Teo, John L. Hopper, Graham G. Giles, MC Southey, Ingrid Winship, Tu Nguyen-Dumont, and Bernard J. Pope
Subjects: Genetics, education.field_of_study, Massive parallel sequencing, lcsh:QH426-470, PALB2, Population, Pedigree chart, Biology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, Genetic analysis, lcsh:Genetics, Risk Estimate, Oncology, Meeting Abstract, Mutation (genetic algorithm), education, Genetics (clinical), Exome sequencing
Abstract: PALB2 is a breast cancer (BC) susceptibility gene. Its product is the binding partner of BRCA1 and BRCA2 and is involved in DNA repair. Studies of multiple-case BC families have reported that truncating mono-allelic PALB2 mutations, on average, increase BC risk two to six fold. Our recent population-based study estimated that carriers of PALB2 c.3113G>A had a cumulative BC risk of carrying PALB2 c.3113G>A to be 91% (95%CI=41-100) by age 70, comparable to 65% (95%CI=44-78) and 45% (95%CI=31-56) average risk estimates for BRCA1 and BRCA2 mutation carriers respectively. One of these pedigrees used for the above estimation, extensively screened but not found to carry a BRCA1 or BRCA2 mutation, exhibited ten diagnoses of BC, including five under 50 years of age, and a pedigree structure that does not allow for all cases to be explained by a single genetic factor. In view of such a high risk estimate and the observations of BC in non-PALB2 mutation carriers in this and other pedigrees, we hypothesise that there may be other genetic risk factors segregating through this family. Several genetic modifiers of BC risk have been verified in BRCA1 and BRCA2 mutation carriers. Although these genetic modifiers are associated with small changes in risk individually, collectively they may account for considerable risk modification for some women. Other moderate to highly penetrant genetic factors could also influence risk in BRCA1 and BRCA2 mutation carriers and non-carriers in BC families harbouring such genetic variants. Similarly, the presence of other genetic factors in the subject PALB2 c.3113G>A pedigree of this study, could alter the risk for mutation carriers and/or convey BC risk to non-PALB2 mutation carriers. Such additional factors could further explain the multiple cases of early onset BC and the high estimated risk of PALB2 c.3113G>A in this family. Whole exome capture followed by massively parallel sequencing was performed on four strategically selected affected females of this family. We have shortlisted 15 variants in this family predicted to be protein damaging by SIFT in genes with plausible relevance to cancer aetiology. Eight such variants are predicted to result in protein truncation or are variants predicted to have strong effects on splicing efficiency, one of which have been observed in key DNA repair genes. Six of the genes have roles in DNA repair, three in cell cycle checkpoint regulation, one controls telomerase activity and another has been reported to be a prostate cancer predisposition gene. Further analyses of these candidate BC predisposition genes will be presented.
Published: 2012
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40. Genome-wide association analysis identifies three new breast cancer susceptibility loci

Author: William J. Tapper, Frederik Marmé, Natalia Bogdanova, Joe Dennis, Pei-Ei Wu, Vesa Kataja, Michael Jones, Dong-Young Noh, Xiaoqing Chen, Thilo Dörk, Javier Benitez, Arif B. Ekici, André G. Uitterlinden, Karin Leunen, Chen-Yang Shen, Esther M. John, Sune F. Nielsen, Adam M. Lee, Arto Mannermaa, Dieter Flesch-Janys, Diana Eccles, Don M. Conroy, Quinten Waisfisz, Sara Margolin, Hoda Anton-Culver, Peter Devilee, Ans M.W. van den Ouweland, Ruth Swann, Chia-Ni Hsiung, Peter Schürmann, Per Hall, Bertram Müller-Myhsok, Jonathan Beesley, Graham G. Giles, Qin Wang, Mitul Shah, Matthias W. Beckmann, Veli-Matti Kosma, Carmel Apicella, Henrik Flyger, Daniel F. Schmidt, Gianluca Severi, Kristen N. Stevens, Paolo Peterlongo, Helen Tsimiklis, Betül T. Yesilyurt, Irene L. Andrulis, Louiza S. Velentzis, Peter A. Fasching, Jyh-Cherng Yu, Caroline Baynes, Jenny Chang-Claude, Craig Luccarini, Leslie Bernstein, Katarzyna Durda, Antoinette Hollestelle, Catriona McLean, Georgia Chenevix-Trench, Rebecca Hein, Heli Nevanlinna, Arja Jukkola-Vuorinen, Jolanta Lissowska, Rita K. Schmutzler, Giuseppe Floris, Christa Stegmaier, David J. Hunter, Kristiina Aittomäki, Johann H. Karstens, Alan Ashworth, Alfons Meindl, Emilie Cordina-Duverger, Stefan Nickels, Julian Peto, Jan Lubinski, Børge G. Nordestgaard, Ed Dicks, Stig E. Bojesen, Christie J. van Asperen, Malcolm W.R. Reed, Michael J. Kerin, Annika Lindblom, Barbara Burwinkel, Kristy Driver, Darya Prokofieva, Montserrat Garcia-Closas, Thomas Brüning, Christina Justenhoven, Nazneen Rahman, Annegien Broeks, Hermann Brenner, Hiltrud Brauch, Laura Baglietto, Yuri I. Rogov, Clare Turnbull, A Jakubowska, Marina Bermisheva, Heiko Müller, Hanne Meijers-Heijboer, Anne-Lise Børrensen-Dale, Pascal Guénel, Stephen J. Chanock, Siranoush Manoukian, Melissa C. Southey, Daniel J. Park, M. Rosario Alonso, Christof Sohn, Shan Wang-Gohrke, Melanie Maranian, Shahana Ahmed, Jonine D. Figueroa, Robert Winqvist, Jianjun Liu, Suthee Rattanamongkongul, Diether Lambrechts, Andreas Schneeweiss, Paul D.P. Pharoah, Alexander Miron, Ursula Eilber, Angela Cox, Anna González-Neira, Minh Bui, Frans B. L. Hogervorst, Peter Hillemanns, Peter Lichtner, Maartje J. Hooning, Roger L. Milne, Alison M. Dunning, Fernando Rivadeneira, Ian Tomlinson, Thérèse Truong, Volker Arndt, Rogier A. Oldenburg, Grethe I. Grenaker Alnæs, Senno Verhoef, Rob A. E. M. Tollenaar, Anna Marie Mulligan, Kenneth Muir, Christina Clarke Dur, Katarzyna Jaworska, Saila Kauppila, Olivia Fletcher, Jaana M. Hartikainen, Michael P. Lux, Kyriaki Michailidou, Stefano Fortuzzi, Douglas F. Easton, Anthony J. Swerdlow, Elza Khusnutdinova, Annie Perkins, Carl Blomqvist, Argyrios Ziogas, Keun-Young Yoo, Caroline Seynaeve, Natalia Antonenkova, Bruce A.J. Ponder, Vessela N. Kristensen, Gord Glendon, Daehee Kang, Elinor J. Sawyer, Michael Bremer, Louise A. Brinton, Minouk J. Schoemaker, Kamila Czene, Isabel dos Santos Silva, John L. Hopper, Astrid K. Irwanto, Nick Orr, S Gerty, Fergus J. Couch, Arkom Chaiwerawattana, Manjeet K. Humphreys, Marjanka K. Schmidt, Maya Ghoussaini, Nikki Graham, Artitaya Lophatananon, Florence Menegaux, Enes Makalic, Katri Pylkäs, Nichola Johnson, Xianshu Wang, Bernardo Bonanni, Mark Lathrop, Human genetics, CCA - Oncogenesis, Clinical Genetics, Internal Medicine, Medical Oncology, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, and Human Genetics
Subjects: Candidate gene, Chromosomes,Human,Pair 21, analysis, cell carcinoma, Mammary gland, Estrogen receptor, Genome-wide association study, developmental regulatory molecule, 0302 clinical medicine, common variants, retinoic acid, Pair 12, genetics, hormone-related protein, Genetics, Chromosomes,Human,Pair 12, Treatment - Localised Therapies – Discovery and Development, Principal Component Analysis, 0303 health sciences, Bone metastasis, Single Nucleotide, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, epidemiology, Cancer Type - Breast Cancer, Female, Human, Risk, ulnar-mammary syndrome, parathyroid-hormone, European Continental Ancestry Group, Breast Neoplasms, Biology, Chromosomes, Polymorphism,Single Nucleotide, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Genetic predisposition, medicine, cancer, Humans, Women, Genetic Predisposition to Disease, Polymorphism, Genetics and epigenetic pathways of disease Translational research [NCMLS 6], breast, 030304 developmental biology, Hereditary cancer and cancer-related syndromes [ONCOL 1], Cancer, confer susceptibility, medicine.disease, gene-expression, Logistic Models, negative-feedback, Genetic Loci, Cancer research, Other, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 21, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Pair 21, Meta-Analysis
Abstract: Item does not contain fulltext Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for approximately 8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in approximately 70,000 cases and approximately 68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 x 10(-35)), 12q24 (rs1292011; P = 4.3 x 10(-19)) and 21q21 (rs2823093; P = 1.1 x 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.
Published: 2012
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41. Hi-Plex for high-throughput mutation screening: application to the breast cancer susceptibility gene PALB2

Author: William D. Foulkes, Zhi Ling Teo, Helen Tsimiklis, John L. Hopper, Maryam Mahmoodi, Fleur Hammet, Daniel J. Park, Graham G. Giles, Nelly Sabbaghian, Marc Tischkowitz, Melissa C. Southey, Bernard J. Pope, and Tu Nguyen-Dumont
Subjects: Massively parallel sequencing, DNA Mutational Analysis, Breast Neoplasms, Biology, Hi-Plex, Mutation screening, Melting curve analysis, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, TaqMan, Molecular diagnostics, Genetics, Humans, Genetic Predisposition to Disease, Genetics(clinical), Genetics (clinical), 030304 developmental biology, Sanger sequencing, 0303 health sciences, Massive parallel sequencing, Tumor Suppressor Proteins, High-Throughput Nucleotide Sequencing, Nuclear Proteins, Ion semiconductor sequencing, Amplicon, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Mutation, PALB2, symbols, Female, Fanconi Anemia Complementation Group N Protein, Research Article
Abstract: Background Massively parallel sequencing (MPS) has revolutionised biomedical research and offers enormous capacity for clinical application. We previously reported Hi-Plex, a streamlined highly-multiplexed PCR-MPS approach, allowing a given library to be sequenced with both the Ion Torrent and TruSeq chemistries. Comparable sequencing efficiency was achieved using material derived from lymphoblastoid cell lines and formalin-fixed paraffin-embedded tumour. Methods Here, we report high-throughput application of Hi-Plex by performing blinded mutation screening of the coding regions of the breast cancer susceptibility gene PALB2 on a set of 95 blood-derived DNA samples that had previously been screened using Sanger sequencing and high-resolution melting curve analysis (n = 90), or genotyped by Taqman probe-based assays (n = 5). Hi-Plex libraries were prepared simultaneously using relatively inexpensive, readily available reagents in a simple half-day protocol followed by MPS on a single MiSeq run. Results We observed that 99.93% of amplicons were represented at ≥10X coverage. All 56 previously identified variant calls were detected and no false positive calls were assigned. Four additional variant calls were made and confirmed upon re-analysis of previous data or subsequent Sanger sequencing. Conclusions These results support Hi-Plex as a powerful approach for rapid, cost-effective and accurate high-throughput mutation screening. They further demonstrate that Hi-Plex methods are suitable for and can meet the demands of high-throughput genetic testing in research and clinical settings.
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