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1. Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci

Author: Hongjie Chen, Shaoqi Fan, Jennifer Stone, Deborah J. Thompson, Julie Douglas, Shuai Li, Christopher Scott, Manjeet K. Bolla, Qin Wang, Joe Dennis, Kyriaki Michailidou, Christopher Li, Ulrike Peters, John L. Hopper, Melissa C. Southey, Tu Nguyen-Dumont, Tuong L. Nguyen, Peter A. Fasching, Annika Behrens, Gemma Cadby, Rachel A. Murphy, Kristan Aronson, Anthony Howell, Susan Astley, Fergus Couch, Janet Olson, Roger L. Milne, Graham G. Giles, Christopher A. Haiman, Gertraud Maskarinec, Stacey Winham, Esther M. John, Allison Kurian, Heather Eliassen, Irene Andrulis, D. Gareth Evans, William G. Newman, Per Hall, Kamila Czene, Anthony Swerdlow, Michael Jones, Marina Pollan, Pablo Fernandez-Navarro, Daniel S. McConnell, Vessela N. Kristensen, NBCS Investigators, Joseph H. Rothstein, Pei Wang, Laurel A. Habel, Weiva Sieh, Alison M. Dunning, Paul D. P. Pharoah, Douglas F. Easton, Gretchen L. Gierach, Rulla M. Tamimi, Celine M. Vachon, and Sara Lindström
Subjects: Mammographic density, Breast cancer, Genome-wide association study (GWAS), Transcriptome-wide association study (TWAS), Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. Methods We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. Results We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p
Published: 2022
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2. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Author: Yan Dora Zhang, Amber N. Hurson, Haoyu Zhang, Parichoy Pal Choudhury, Douglas F. Easton, Roger L. Milne, Jacques Simard, Per Hall, Kyriaki Michailidou, Joe Dennis, Marjanka K. Schmidt, Jenny Chang-Claude, Puya Gharahkhani, David Whiteman, Peter T. Campbell, Michael Hoffmeister, Mark Jenkins, Ulrike Peters, Li Hsu, Stephen B. Gruber, Graham Casey, Stephanie L. Schmit, Tracy A. O’Mara, Amanda B. Spurdle, Deborah J. Thompson, Ian Tomlinson, Immaculata De Vivo, Maria Teresa Landi, Matthew H. Law, Mark M. Iles, Florence Demenais, Rajiv Kumar, Stuart MacGregor, D. Timothy Bishop, Sarah V. Ward, Melissa L. Bondy, Richard Houlston, John K. Wiencke, Beatrice Melin, Jill Barnholtz-Sloan, Ben Kinnersley, Margaret R. Wrensch, Christopher I. Amos, Rayjean J. Hung, Paul Brennan, James McKay, Neil E. Caporaso, Sonja I. Berndt, Brenda M. Birmann, Nicola J. Camp, Peter Kraft, Nathaniel Rothman, Susan L. Slager, Andrew Berchuck, Paul D. P. Pharoah, Thomas A. Sellers, Simon A. Gayther, Celeste L. Pearce, Ellen L. Goode, Joellen M. Schildkraut, Kirsten B. Moysich, Laufey T. Amundadottir, Eric J. Jacobs, Alison P. Klein, Gloria M. Petersen, Harvey A. Risch, Rachel Z. Stolzenberg-Solomon, Brian M. Wolpin, Donghui Li, Rosalind A. Eeles, Christopher A. Haiman, Zsofia Kote-Jarai, Fredrick R. Schumacher, Ali Amin Al Olama, Mark P. Purdue, Ghislaine Scelo, Marlene D. Dalgaard, Mark H. Greene, Tom Grotmol, Peter A. Kanetsky, Katherine A. McGlynn, Katherine L. Nathanson, Clare Turnbull, Fredrik Wiklund, Breast Cancer Association Consortium (BCAC), Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON), Colon Cancer Family Registry (CCFR), Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT), Endometrial Cancer Association Consortium (ECAC), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Melanoma Genetics Consortium (GenoMEL), Glioma International Case-Control Study (GICC), International Lung Cancer Consortium (ILCCO), Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph), Ovarian Cancer Association Consortium (OCAC), Oral Cancer GWAS, Pancreatic Cancer Case-Control Consortium (PanC4), Pancreatic Cancer Cohort Consortium (PanScan), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL), Renal Cancer GWAS, Testicular Cancer Consortium (TECAC), Stephen J. Chanock, Nilanjan Chatterjee, and Montserrat Garcia-Closas
Subjects: Science
Abstract: In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.
Published: 2020
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3. Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan

Author: Ben Hollis, Felix R. Day, Alexander S. Busch, Deborah J. Thompson, Ana Luiza G. Soares, Paul R. H. J. Timmers, Alex Kwong, Doug F. Easton, Peter K. Joshi, Nicholas J. Timpson, The PRACTICAL Consortium, andMe Research Team, Ken K. Ong, and John R. B. Perry
Subjects: Science
Abstract: Age at voice-breaking is used to determine puberty timing in men, recall of which is considered less accurate than age at first menarche in women. Here, the authors perform multi-trait GWAS for male puberty timing by including both age at voice breaking and age of first facial hair for improved phenotype definition and power.
Published: 2020
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4. Joint association of mammographic density adjusted for age and body mass index and polygenic risk score with breast cancer risk

Author: Celine M. Vachon, Christopher G. Scott, Rulla M. Tamimi, Deborah J. Thompson, Peter A. Fasching, Jennifer Stone, Melissa C. Southey, Stacey Winham, Sara Lindström, Jenna Lilyquist, Graham G. Giles, Roger L. Milne, Robert J. MacInnis, Laura Baglietto, Jingmei Li, Kamila Czene, Manjeet K. Bolla, Qin Wang, Joe Dennis, Lothar Haeberle, Mikael Eriksson, Peter Kraft, Robert Luben, Nick Wareham, Janet E. Olson, Aaron Norman, Eric C. Polley, Gertraud Maskarinec, Loic Le Marchand, Christopher A. Haiman, John L. Hopper, Fergus J. Couch, Douglas F. Easton, Per Hall, Nilanjan Chatterjee, and Montse Garcia-Closas
Subjects: Breast density, Breast cancer risk, Polygenic risk score, Genetic variation, Risk models, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Mammographic breast density, adjusted for age and body mass index, and a polygenic risk score (PRS), comprised of common genetic variation, are both strong risk factors for breast cancer and increase discrimination of risk models. Understanding their joint contribution will be important to more accurately predict risk. Methods Using 3628 breast cancer cases and 5126 controls of European ancestry from eight case-control studies, we evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS and quantitative mammographic density measures with breast cancer. Mammographic percent density and absolute dense area were evaluated using thresholding software and examined as residuals after adjusting for age, 1/BMI, and study. PRS and adjusted density phenotypes were modeled both continuously (per 1 standard deviation, SD) and categorically. We fit logistic regression models and tested the null hypothesis of multiplicative joint associations for PRS and adjusted density measures using likelihood ratio and global and tail-based goodness of fit tests within the subset of six cohort or population-based studies. Results Adjusted percent density (odds ratio (OR) = 1.45 per SD, 95% CI 1.38–1.52), adjusted absolute dense area (OR = 1.34 per SD, 95% CI 1.28–1.41), and the 77-SNP PRS (OR = 1.52 per SD, 95% CI 1.45–1.59) were associated with breast cancer risk. There was no evidence of interaction of the PRS with adjusted percent density or dense area on risk of breast cancer by either the likelihood ratio (P > 0.21) or goodness of fit tests (P > 0.09), whether assessed continuously or categorically. The joint association (OR) was 2.60 in the highest categories of adjusted PD and PRS and 0.34 in the lowest categories, relative to women in the second density quartile and middle PRS quintile. Conclusions The combined associations of the 77-SNP PRS and adjusted density measures are generally well described by multiplicative models, and both risk factors provide independent information on breast cancer risk.
Published: 2019
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5. Identification of nine new susceptibility loci for endometrial cancer

Author: Tracy A. O’Mara, Dylan M. Glubb, Frederic Amant, Daniela Annibali, Katie Ashton, John Attia, Paul L. Auer, Matthias W. Beckmann, Amanda Black, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, Louise Brinton, Daniel D. Buchanan, Barbara Burwinkel, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, Maxine M. Chen, Timothy H. T. Cheng, Christine L. Clarke, Mark Clendenning, Linda S. Cook, Fergus J. Couch, Angela Cox, Marta Crous-Bous, Kamila Czene, Felix Day, Joe Dennis, Jeroen Depreeuw, Jennifer Anne Doherty, Thilo Dörk, Sean C. Dowdy, Matthias Dürst, Arif B. Ekici, Peter A. Fasching, Brooke L. Fridley, Christine M. Friedenreich, Lin Fritschi, Jenny Fung, Montserrat García-Closas, Mia M. Gaudet, Graham G. Giles, Ellen L. Goode, Maggie Gorman, Christopher A. Haiman, Per Hall, Susan E. Hankison, Catherine S. Healey, Alexander Hein, Peter Hillemanns, Shirley Hodgson, Erling A. Hoivik, Elizabeth G. Holliday, John L. Hopper, David J. Hunter, Angela Jones, Camilla Krakstad, Vessela N. Kristensen, Diether Lambrechts, Loic Le Marchand, Xiaolin Liang, Annika Lindblom, Jolanta Lissowska, Jirong Long, Lingeng Lu, Anthony M. Magliocco, Lynn Martin, Mark McEvoy, Alfons Meindl, Kyriaki Michailidou, Roger L. Milne, Miriam Mints, Grant W. Montgomery, Rami Nassir, Håkan Olsson, Irene Orlow, Geoffrey Otton, Claire Palles, John R. B. Perry, Julian Peto, Loreall Pooler, Jennifer Prescott, Tony Proietto, Timothy R. Rebbeck, Harvey A. Risch, Peter A. W. Rogers, Matthias Rübner, Ingo Runnebaum, Carlotta Sacerdote, Gloria E. Sarto, Fredrick Schumacher, Rodney J. Scott, V. Wendy Setiawan, Mitul Shah, Xin Sheng, Xiao-Ou Shu, Melissa C. Southey, Anthony J. Swerdlow, Emma Tham, Jone Trovik, Constance Turman, Jonathan P. Tyrer, Celine Vachon, David VanDen Berg, Adriaan Vanderstichele, Zhaoming Wang, Penelope M. Webb, Nicolas Wentzensen, Henrica M. J. Werner, Stacey J. Winham, Alicja Wolk, Lucy Xia, Yong-Bing Xiang, Hannah P. Yang, Herbert Yu, Wei Zheng, Paul D. P. Pharoah, Alison M. Dunning, Peter Kraft, Immaculata De Vivo, Ian Tomlinson, Douglas F. Easton, Amanda B. Spurdle, and Deborah J. Thompson
Subjects: Science
Abstract: Endometrial cancer is the most common invasive gynaecological cancer in developed countries. Here a meta-analysis identifies an additional nine novel endometrial cancer risk loci and eQTL analysis reveals risk variants associate with reduced expression of negative regulators of oncogenic signal transduction proteins.
Published: 2018
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6. Genetic overlap between endometriosis and endometrial cancer: evidence from cross‐disease genetic correlation and GWAS meta‐analyses

Author: Jodie N. Painter, Tracy A. O'Mara, Andrew P. Morris, Timothy H. T. Cheng, Maggie Gorman, Lynn Martin, Shirley Hodson, Angela Jones, Nicholas G. Martin, Scott Gordon, Anjali K. Henders, John Attia, Mark McEvoy, Elizabeth G. Holliday, Rodney J. Scott, Penelope M. Webb, Peter A. Fasching, Matthias W. Beckmann, Arif B. Ekici, Alexander Hein, Matthias Rübner, Per Hall, Kamila Czene, Thilo Dörk, Matthias Dürst, Peter Hillemanns, Ingo Runnebaum, Diether Lambrechts, Frederic Amant, Daniela Annibali, Jeroen Depreeuw, Adriaan Vanderstichele, Ellen L. Goode, Julie M. Cunningham, Sean C. Dowdy, Stacey J. Winham, Jone Trovik, Erling Hoivik, Henrica M. J. Werner, Camilla Krakstad, Katie Ashton, Geoffrey Otton, Tony Proietto, Emma Tham, Miriam Mints, Shahana Ahmed, Catherine S. Healey, Mitul Shah, Paul D. P. Pharoah, Alison M. Dunning, Joe Dennis, Manjeet K. Bolla, Kyriaki Michailidou, Qin Wang, Jonathan P. Tyrer, John L. Hopper, Julian Peto, Anthony J. Swerdlow, Barbara Burwinkel, Hermann Brenner, Alfons Meindl, Hiltrud Brauch, Annika Lindblom, Jenny Chang‐Claude, Fergus J. Couch, Graham G. Giles, Vessela N. Kristensen, Angela Cox, Krina T. Zondervan, Dale R. Nyholt, Stuart MacGregor, Grant W. Montgomery, Ian Tomlinson, Douglas F. Easton, Deborah J. Thompson, and Amanda B. Spurdle
Subjects: Cross‐disease analysis, endometrial cancer, endometriosis, genome‐wide association study, genetic correlation, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (rg = 0.23, P = 9.3 × 10−3), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10−3) and concordance in effect direction (P = 2.0 × 10−3) between the two diseases. Cross‐disease GWAS meta‐analysis highlighted 13 distinct loci associated at P ≤ 10−5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10−8, OR = 1.11, 95% CI = 1.07–1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross‐disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.
Published: 2018
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7. Assessing the Role of Selenium in Endometrial Cancer Risk: A Mendelian Randomization Study

Author: Pik Fang Kho, Dylan M. Glubb, Deborah J. Thompson, Amanda B. Spurdle, and Tracy A. O'Mara
Subjects: Mendelian randomization, endometrial cancer, toenail selenium, circulating selenium, genome-wide association study, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Endometrial cancer is the most commonly diagnosed gynecological cancer in developed countries. Based on evidence from observational studies which suggest selenium inhibits the development of several cancers (including lung and prostate cancer), selenium supplementation has been touted as a potential cancer preventative agent. However, randomized controlled trials have not reported benefit for selenium supplementation in reducing cancer risk. For endometrial cancer, limited observational studies have been conducted assessing whether selenium intake, or blood selenium levels, associated with reduced risk, and no randomized controlled trials have been conducted. We performed a two-sample Mendelian randomization analysis to examine the relationship between selenium levels (using a composite measure of blood and toenail selenium) and endometrial cancer risk, using summary statistics for four genetic variants associated with selenium levels at genome-wide significance levels (P < 5 × 10−8), from a study of 12,906 endometrial cancer cases and 108,979 controls, all of European ancestry. Inverse variance weighted (IVW) analysis indicated no evidence of a causal role for selenium levels in endometrial cancer development (OR per unit increase in selenium levels Z-score = 0.99, 95% CI = 0.87–1.14). Similar results were observed for sensitivity analyses robust to the presence of unknown pleiotropy (OR per unit increase in selenium levels Z-score = 0.98, 95% CI 0.89–1.08 for weighted median; OR per unit increase in selenium levels Z-score = 0.90, 95% CI = 0.53–1.50 for MR-Egger). In conclusion, these results do not support the use of selenium supplementation to prevent endometrial cancer.
Published: 2019
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8. Development and evaluation of polygenic risk scores for prediction of endometrial cancer risk in European women

Author: Cemsel Bafligil, Deborah J. Thompson, Artitaya Lophatananon, Neil A.J. Ryan, Miriam J. Smith, Joe Dennis, Krisztina Mekli, Tracy A. O’Mara, D. Gareth Evans, and Emma J. Crosbie
Subjects: Multifactorial Inheritance, Risk Factors, Humans, Female, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Risk Assessment, Genetics (clinical), Endometrial Neoplasms, Genome-Wide Association Study
Abstract: Single-nucleotide variations (SNVs) (formerly single-nucleotide polymorphism [SNV]) influence genetic predisposition to endometrial cancer. We hypothesized that a polygenic risk score (PRS) comprising multiple SNVs may improve endometrial cancer risk prediction for targeted screening and prevention.We developed PRSs from SNVs identified from a systematic review of published studies and suggestive SNVs from the Endometrial Cancer Association Consortium. These were tested in an independent study of 555 surgically-confirmed endometrial cancer cases and 1202 geographically-matched controls from Manchester, United Kingdom and validated in 1676 cases and 116,960 controls from the UK Biobank (UKBB).Age and body mass index predicted endometrial cancer in both data sets (Manchester: area under the receiver operator curve [AUC] = 0.77, 95% CI = 0.74-0.80; UKBB: AUC = 0.74, 95% CI = 0.73-0.75). The AUC for PRS19, PRS24, and PRS72 were 0.58, 0.55, and 0.57 in the Manchester study and 0.56, 0.54, and 0.54 in UKBB, respectively. For PRS19, women in the third tertile had a 2.1-fold increased risk of endometrial cancer compared with those in the first tertile of the Manchester study (odds ratio = 2.08, 95% CI = 1.61-2.68, PAn endometrial cancer risk prediction model incorporating a PRS derived from multiple SNVs may help stratify women for screening and prevention strategies.
Published: 2022

9. Supplementary Grant Support from Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author: Diether Lambrechts, Paul D.P. Pharoah, Rosalind Eeles, Georgia Chenevix-Trench, Douglas F. Easton, Simon A. Gayther, Per Hall, Fergus J. Couch, Stephen J. Chanock, Peter Kraft, Brian E. Henderson, David J. Hunter, Thomas A. Sellers, Amanda Spurdle, Christopher A. Haiman, Jacques Simard, Alison M. Dunning, Andrew Berchuck, Matthew L. Freedman, Fredrick Schumacher, Yu-Tang Gao, Xiao-Ou Shu, Wojciech Kluzniak, William J. Blot, Weiva Sieh, Wei Zheng, Walther Vogel, Volker Arndt, Vessela Kristensen, Veronica Wendy Setiawan, Veli-Matti Kosma, Vanio Mitev, Ute Hamann, Usha Menon, Todd L. Edwards, Tim J. Key, Tiina Wahlfors, Thomas Brüning, Thilo Dörk, Teuvo L.J. Tammela, Tanja Pejovic, Susanne Krüger Kjær, Susan M. Gapstur, Stig E. Bojesen, Stephen N. Thibodeau, Soo-Hwang Teo, Soo Chin Lee, Sonja Berndt, Sofia Maia, Shelley S. Tworoger, Shannon K. McDonnell, Sara H. Olson, Sara Benlloch, Ruth C. Travis, Roger L. Milne, Roberta Ness, Robert Winqvist, Robert N. Hoover, Robert J. MacInnis, Robert A. Stephenson, Rita K. Schmutzler, Reidun Kristin Kopperud, Ralf Butzow, Radka Kaneva, Qiyuan Li, Qiuyin Cai, Qin Wang, Peter Devilee, Peter A. Fasching, Per Broberg, Penelope M. Webb, Paula Paulo, Paul Brennan, Pascal Guénel, Paolo Peterlongo, Nora Pashayan, Nicolas Wentzensen, Nick Orr, Nhu D. Le, Nazneen Rahman, Natalia Bogdanova, Montserrat Garcia-Closas, Minouk J. Schoemaker, Ming-Feng Hou, Michelle A.T. Hildebrandt, Michael Lush, Michael Jones, Melissa C. Southey, Maureen Sanderson, Matthieu Moisse, Matthias W. Beckmann, Mary Anne Rossing, Markus Aly, Marjorie Riggan, Marjanka K. Schmidt, Marc T. Goodman, Manuel R. Teixeira, Manuel Luedeke, Manjeet K. Bolla, Malcolm C. Pike, Maartje J. Hooning, Lisa Cannon-Albright, Linda S. Cook, Liesel M. Fitzgerald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Kunle Odunsi, Kristiina Aittomäki, Kirsten B. Moysich, Kexin Chen, Kenneth Offitt, Kenneth Muir, Keitaro Matsuo, Kay-Tee Khaw, Kathleen Herkommer, Karen H. Lu, Kamila Czene, Jyotsna Batra, Julio Pow-Sang, Julie M. Cunningham, Julian Peto, Julia A. Knight, Judith A. Clements, Jonine Figueroa, Jong Y. Park, Jolanta Kupryjanczyk, John L. Hopper, Johanna Schleutker, Joellen M. Schildkraut, Joe Dennis, Jenny L. Donovan, Jenny Chang-Claude, Jennifer B. Permuth, Jennifer A. Doherty, Javier Benítez, Janet L. Stanford, Jan Lubiński, Jacek Gronwald, Ignace Vergote, Ian Campbell, Iain McNeish, Hui-Yi Lim, Honglin Song, Hoda Anton-Culver, Hiltrud Brauch, Hermann Brenner, Henrik Gronberg, Heli Nevanlinna, Helga B. Salvesen, Hatef Darabi, Harvey A. Risch, Hardev Pandha, Hans-Ulrich Ulmer, Hans Wildiers, Håkan Olsson, Graham G. Giles, Fredrik Wiklund, Freddie C. Hamdy, Francesmary Modugno, Florian Heitz, Fiona Bruinsma, Fengju Song, Estrid Høgdall, Elza Khusnutdinova, Ellen L. Goode, Elizabeth M. Poole, Elisa V. Bandera, Elinor J. Sawyer, Drakoulis Yannoukakos, Douglas A. Levine, Dominika Wokozorczyk, Digna R. Velez Edwards, Dieter Flesch-Janys, Diana Eccles, David E. Neal, Daniel W. Cramer, Daniel O. Stram, Daniel J. Schaid, Daniel C. Tessier, Daehee Kang, Craig C. Teerlink, Claus K. Høgdall, Christine B. Ambrosone, Christiane Maier, Christa Stegmaier, Chavdar Slavov, Cezary Cybulski, Celine Vachon, Celeste Leigh Pearce, Catriona McLean, Catherine Phelan, Carl Blomqvist, Børge G. Nordestgaard, Beth Y. Karlan, Barbara Burwinkel, Arif B. Ekici, Argyrios Ziogas, Anthony Swerdlow, Annika Lindblom, Anna H. Wu, Anna Gonzalez-Neira, Anja Rudolph, Angela Cox, Andrzej Kierzek, Ana Peixoto, Alvaro Monteiro, Alicja Wolk, Alice S. Whittemore, Aleksandra Gentry-Maharaj, Aida K. Dieffenbach, Agnieszka Michael, Agnieszka Dansonka-Mieszkowska, Adam S. Kibel, Deborah J. Thompson, Susan J. Ramus, Sara Lindstrom, Kate Lawrenson, ZSofia Kote-Jarai, Jonathan Tyrer, Kyriaki Michailidou, Ali Amin Al Olama, Jonathan Beesley, and Siddhartha P. Kar
Abstract: Supplementary Grant Support
Published: 2023

10. Supplementary Methods, Figures S1 - S3 from Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author: Diether Lambrechts, Paul D.P. Pharoah, Rosalind Eeles, Georgia Chenevix-Trench, Douglas F. Easton, Simon A. Gayther, Per Hall, Fergus J. Couch, Stephen J. Chanock, Peter Kraft, Brian E. Henderson, David J. Hunter, Thomas A. Sellers, Amanda Spurdle, Christopher A. Haiman, Jacques Simard, Alison M. Dunning, Andrew Berchuck, Matthew L. Freedman, Fredrick Schumacher, Yu-Tang Gao, Xiao-Ou Shu, Wojciech Kluzniak, William J. Blot, Weiva Sieh, Wei Zheng, Walther Vogel, Volker Arndt, Vessela Kristensen, Veronica Wendy Setiawan, Veli-Matti Kosma, Vanio Mitev, Ute Hamann, Usha Menon, Todd L. Edwards, Tim J. Key, Tiina Wahlfors, Thomas Brüning, Thilo Dörk, Teuvo L.J. Tammela, Tanja Pejovic, Susanne Krüger Kjær, Susan M. Gapstur, Stig E. Bojesen, Stephen N. Thibodeau, Soo-Hwang Teo, Soo Chin Lee, Sonja Berndt, Sofia Maia, Shelley S. Tworoger, Shannon K. McDonnell, Sara H. Olson, Sara Benlloch, Ruth C. Travis, Roger L. Milne, Roberta Ness, Robert Winqvist, Robert N. Hoover, Robert J. MacInnis, Robert A. Stephenson, Rita K. Schmutzler, Reidun Kristin Kopperud, Ralf Butzow, Radka Kaneva, Qiyuan Li, Qiuyin Cai, Qin Wang, Peter Devilee, Peter A. Fasching, Per Broberg, Penelope M. Webb, Paula Paulo, Paul Brennan, Pascal Guénel, Paolo Peterlongo, Nora Pashayan, Nicolas Wentzensen, Nick Orr, Nhu D. Le, Nazneen Rahman, Natalia Bogdanova, Montserrat Garcia-Closas, Minouk J. Schoemaker, Ming-Feng Hou, Michelle A.T. Hildebrandt, Michael Lush, Michael Jones, Melissa C. Southey, Maureen Sanderson, Matthieu Moisse, Matthias W. Beckmann, Mary Anne Rossing, Markus Aly, Marjorie Riggan, Marjanka K. Schmidt, Marc T. Goodman, Manuel R. Teixeira, Manuel Luedeke, Manjeet K. Bolla, Malcolm C. Pike, Maartje J. Hooning, Lisa Cannon-Albright, Linda S. Cook, Liesel M. Fitzgerald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Kunle Odunsi, Kristiina Aittomäki, Kirsten B. Moysich, Kexin Chen, Kenneth Offitt, Kenneth Muir, Keitaro Matsuo, Kay-Tee Khaw, Kathleen Herkommer, Karen H. Lu, Kamila Czene, Jyotsna Batra, Julio Pow-Sang, Julie M. Cunningham, Julian Peto, Julia A. Knight, Judith A. Clements, Jonine Figueroa, Jong Y. Park, Jolanta Kupryjanczyk, John L. Hopper, Johanna Schleutker, Joellen M. Schildkraut, Joe Dennis, Jenny L. Donovan, Jenny Chang-Claude, Jennifer B. Permuth, Jennifer A. Doherty, Javier Benítez, Janet L. Stanford, Jan Lubiński, Jacek Gronwald, Ignace Vergote, Ian Campbell, Iain McNeish, Hui-Yi Lim, Honglin Song, Hoda Anton-Culver, Hiltrud Brauch, Hermann Brenner, Henrik Gronberg, Heli Nevanlinna, Helga B. Salvesen, Hatef Darabi, Harvey A. Risch, Hardev Pandha, Hans-Ulrich Ulmer, Hans Wildiers, Håkan Olsson, Graham G. Giles, Fredrik Wiklund, Freddie C. Hamdy, Francesmary Modugno, Florian Heitz, Fiona Bruinsma, Fengju Song, Estrid Høgdall, Elza Khusnutdinova, Ellen L. Goode, Elizabeth M. Poole, Elisa V. Bandera, Elinor J. Sawyer, Drakoulis Yannoukakos, Douglas A. Levine, Dominika Wokozorczyk, Digna R. Velez Edwards, Dieter Flesch-Janys, Diana Eccles, David E. Neal, Daniel W. Cramer, Daniel O. Stram, Daniel J. Schaid, Daniel C. Tessier, Daehee Kang, Craig C. Teerlink, Claus K. Høgdall, Christine B. Ambrosone, Christiane Maier, Christa Stegmaier, Chavdar Slavov, Cezary Cybulski, Celine Vachon, Celeste Leigh Pearce, Catriona McLean, Catherine Phelan, Carl Blomqvist, Børge G. Nordestgaard, Beth Y. Karlan, Barbara Burwinkel, Arif B. Ekici, Argyrios Ziogas, Anthony Swerdlow, Annika Lindblom, Anna H. Wu, Anna Gonzalez-Neira, Anja Rudolph, Angela Cox, Andrzej Kierzek, Ana Peixoto, Alvaro Monteiro, Alicja Wolk, Alice S. Whittemore, Aleksandra Gentry-Maharaj, Aida K. Dieffenbach, Agnieszka Michael, Agnieszka Dansonka-Mieszkowska, Adam S. Kibel, Deborah J. Thompson, Susan J. Ramus, Sara Lindstrom, Kate Lawrenson, ZSofia Kote-Jarai, Jonathan Tyrer, Kyriaki Michailidou, Ali Amin Al Olama, Jonathan Beesley, and Siddhartha P. Kar
Abstract: Supplementary Figure S1. LocusZoom regional association plots for the seven new cross-cancer loci that were > 1 Mb from known index SNPs. Supplementary Figure S2A-B. Box plots showing eQTL associations between (A) rs9375701 and L3MBTL3 in normal breast and prostate tissues and (B) rs8037137 and RCCD1 in normal breast and ovarian tissues. Supplementary Figure S3. Interactions between BCL2L11 and the 32 Biocarta "Death Pathway" genes. Interactions were identified using the GeneMania server. Circles contain gene names, lines represent interactions, and the color of the line indicates a specific type of interaction as listed in the legend.
Published: 2023

11. Supplementary Tables S1 - S10 from Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author: Diether Lambrechts, Paul D.P. Pharoah, Rosalind Eeles, Georgia Chenevix-Trench, Douglas F. Easton, Simon A. Gayther, Per Hall, Fergus J. Couch, Stephen J. Chanock, Peter Kraft, Brian E. Henderson, David J. Hunter, Thomas A. Sellers, Amanda Spurdle, Christopher A. Haiman, Jacques Simard, Alison M. Dunning, Andrew Berchuck, Matthew L. Freedman, Fredrick Schumacher, Yu-Tang Gao, Xiao-Ou Shu, Wojciech Kluzniak, William J. Blot, Weiva Sieh, Wei Zheng, Walther Vogel, Volker Arndt, Vessela Kristensen, Veronica Wendy Setiawan, Veli-Matti Kosma, Vanio Mitev, Ute Hamann, Usha Menon, Todd L. Edwards, Tim J. Key, Tiina Wahlfors, Thomas Brüning, Thilo Dörk, Teuvo L.J. Tammela, Tanja Pejovic, Susanne Krüger Kjær, Susan M. Gapstur, Stig E. Bojesen, Stephen N. Thibodeau, Soo-Hwang Teo, Soo Chin Lee, Sonja Berndt, Sofia Maia, Shelley S. Tworoger, Shannon K. McDonnell, Sara H. Olson, Sara Benlloch, Ruth C. Travis, Roger L. Milne, Roberta Ness, Robert Winqvist, Robert N. Hoover, Robert J. MacInnis, Robert A. Stephenson, Rita K. Schmutzler, Reidun Kristin Kopperud, Ralf Butzow, Radka Kaneva, Qiyuan Li, Qiuyin Cai, Qin Wang, Peter Devilee, Peter A. Fasching, Per Broberg, Penelope M. Webb, Paula Paulo, Paul Brennan, Pascal Guénel, Paolo Peterlongo, Nora Pashayan, Nicolas Wentzensen, Nick Orr, Nhu D. Le, Nazneen Rahman, Natalia Bogdanova, Montserrat Garcia-Closas, Minouk J. Schoemaker, Ming-Feng Hou, Michelle A.T. Hildebrandt, Michael Lush, Michael Jones, Melissa C. Southey, Maureen Sanderson, Matthieu Moisse, Matthias W. Beckmann, Mary Anne Rossing, Markus Aly, Marjorie Riggan, Marjanka K. Schmidt, Marc T. Goodman, Manuel R. Teixeira, Manuel Luedeke, Manjeet K. Bolla, Malcolm C. Pike, Maartje J. Hooning, Lisa Cannon-Albright, Linda S. Cook, Liesel M. Fitzgerald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Kunle Odunsi, Kristiina Aittomäki, Kirsten B. Moysich, Kexin Chen, Kenneth Offitt, Kenneth Muir, Keitaro Matsuo, Kay-Tee Khaw, Kathleen Herkommer, Karen H. Lu, Kamila Czene, Jyotsna Batra, Julio Pow-Sang, Julie M. Cunningham, Julian Peto, Julia A. Knight, Judith A. Clements, Jonine Figueroa, Jong Y. Park, Jolanta Kupryjanczyk, John L. Hopper, Johanna Schleutker, Joellen M. Schildkraut, Joe Dennis, Jenny L. Donovan, Jenny Chang-Claude, Jennifer B. Permuth, Jennifer A. Doherty, Javier Benítez, Janet L. Stanford, Jan Lubiński, Jacek Gronwald, Ignace Vergote, Ian Campbell, Iain McNeish, Hui-Yi Lim, Honglin Song, Hoda Anton-Culver, Hiltrud Brauch, Hermann Brenner, Henrik Gronberg, Heli Nevanlinna, Helga B. Salvesen, Hatef Darabi, Harvey A. Risch, Hardev Pandha, Hans-Ulrich Ulmer, Hans Wildiers, Håkan Olsson, Graham G. Giles, Fredrik Wiklund, Freddie C. Hamdy, Francesmary Modugno, Florian Heitz, Fiona Bruinsma, Fengju Song, Estrid Høgdall, Elza Khusnutdinova, Ellen L. Goode, Elizabeth M. Poole, Elisa V. Bandera, Elinor J. Sawyer, Drakoulis Yannoukakos, Douglas A. Levine, Dominika Wokozorczyk, Digna R. Velez Edwards, Dieter Flesch-Janys, Diana Eccles, David E. Neal, Daniel W. Cramer, Daniel O. Stram, Daniel J. Schaid, Daniel C. Tessier, Daehee Kang, Craig C. Teerlink, Claus K. Høgdall, Christine B. Ambrosone, Christiane Maier, Christa Stegmaier, Chavdar Slavov, Cezary Cybulski, Celine Vachon, Celeste Leigh Pearce, Catriona McLean, Catherine Phelan, Carl Blomqvist, Børge G. Nordestgaard, Beth Y. Karlan, Barbara Burwinkel, Arif B. Ekici, Argyrios Ziogas, Anthony Swerdlow, Annika Lindblom, Anna H. Wu, Anna Gonzalez-Neira, Anja Rudolph, Angela Cox, Andrzej Kierzek, Ana Peixoto, Alvaro Monteiro, Alicja Wolk, Alice S. Whittemore, Aleksandra Gentry-Maharaj, Aida K. Dieffenbach, Agnieszka Michael, Agnieszka Dansonka-Mieszkowska, Adam S. Kibel, Deborah J. Thompson, Susan J. Ramus, Sara Lindstrom, Kate Lawrenson, ZSofia Kote-Jarai, Jonathan Tyrer, Kyriaki Michailidou, Ali Amin Al Olama, Jonathan Beesley, and Siddhartha P. Kar
Abstract: Supplementary Table S1. Known risk loci for each cancer. Supplementary Table S2. Regions where known index SNPs for at least two of the three cancers lie within 1 Mb of each other. Supplementary Table S3. Full results from the meta-analysis of breast, ovarian, and prostate cancer showing the 18 independent loci associated at P < 10-8 with the same direction of effect across all three cancers. Supplementary Table S4. Conditional analysis of the rs1469713 (breast-ovarian-prostate cancer) signal, conditioning on the rs4808801 (breast cancer-specific) signal that was < 1 Mb away using GCTA software. Supplementary Table S5. Most significantly-associated genotyped SNP at new loci where index SNPs were imputed. Supplementary Table S6. Expression QTL analysis results from the GTEx Portal for the new cross-cancer risk loci listed in main Table 2. Supplementary Table S7. SNPs with P < 10-8 at the new cross-cancer risk loci listed in main Table 2 that overlap predicted enhancers in at least two cell types. Supplementary Table S8. HaploReg and non-coding RNA annotation of variants with P < 10-8 at the new cross-cancer risk loci listed in main Table 2. Supplementary Table S9. Eight of the 32 genes involved in induction of apoptosis through DR3 and DR4/5 Death Receptors (MSigDB: Biocarta "Death Pathway") a that were < 1 Mb away from an independent P < 10-5 index SNP in the 3-cancer meta-analysis. Supplementary Table S10. INRICH pathway analysis results for pathways with empirical P < 0.05. Apoptosis-related pathways containing BCL2L11 are shaded.
Published: 2023

12. Supplementary Tables from External Validation of Risk Prediction Models Incorporating Common Genetic Variants for Incident Colorectal Cancer Using UK Biobank

Author: Juliet A. Usher-Smith, Xin Yang, Joe Dennis, Fiona M. Walter, Jon D. Emery, Antonis C. Antoniou, Simon J. Griffin, Luke J. McGeoch, Deborah J. Thompson, Britt Kilian, and Catherine L. Saunders
Abstract: Supplementary Tables
Published: 2023

13. Data from External Validation of Risk Prediction Models Incorporating Common Genetic Variants for Incident Colorectal Cancer Using UK Biobank

Author: Juliet A. Usher-Smith, Xin Yang, Joe Dennis, Fiona M. Walter, Jon D. Emery, Antonis C. Antoniou, Simon J. Griffin, Luke J. McGeoch, Deborah J. Thompson, Britt Kilian, and Catherine L. Saunders
Abstract: The aim of this study was to compare and externally validate risk scores developed to predict incident colorectal cancer that include common genetic variants (SNPs), with or without established lifestyle/environmental (questionnaire-based/classical/phenotypic) risk factors. We externally validated 23 risk models from a previous systematic review in 443,888 participants ages 37 to 73 from the UK Biobank cohort who had 6-year prospective follow-up, no prior history of colorectal cancer, and data for incidence of colorectal cancer through linkage to national cancer registries. There were 2,679 (0.6%) cases of incident colorectal cancer. We assessed model discrimination using the area under the operating characteristic curve (AUC) and relative risk calibration. The AUC of models including only SNPs increased with the number of included SNPs and was similar in men and women: the model by Huyghe with 120 SNPs had the highest AUC of 0.62 [95% confidence interval (CI), 0.59–0.64] in women and 0.64 (95% CI, 0.61–0.66) in men. Adding phenotypic risk factors without age improved discrimination in men but not in women. Adding phenotypic risk factors and age increased discrimination in all cases (P < 0.05), with the best performing models including SNPs, phenotypic risk factors, and age having AUCs between 0.64 and 0.67 in women and 0.67 and 0.71 in men. Relative risk calibration varied substantially across the models. Among middle-aged people in the UK, existing polygenic risk scores discriminate moderately well between those who do and do not develop colorectal cancer over 6 years. Consideration should be given to exploring the feasibility of incorporating genetic and lifestyle/environmental information in any future stratified colorectal cancer screening program.
Published: 2023

14. Supplementary Table Legends from External Validation of Risk Prediction Models Incorporating Common Genetic Variants for Incident Colorectal Cancer Using UK Biobank

Author: Juliet A. Usher-Smith, Xin Yang, Joe Dennis, Fiona M. Walter, Jon D. Emery, Antonis C. Antoniou, Simon J. Griffin, Luke J. McGeoch, Deborah J. Thompson, Britt Kilian, and Catherine L. Saunders
Abstract: Supplementary Table Legends
Published: 2023

15. Supplementary Table 1 from The Heritability of Mammographic Breast Density and Circulating Sex-Hormone Levels: Two Independent Breast Cancer Risk Factors

Author: Deborah J. Thompson, Douglas F. Easton, Mitchell Dowsett, Ruth M.L. Warren, Tina Audley, Jean Leyland, Judith Brown, Elizabeth Folkerd, Paula L. Smith, and Jajini S. Varghese
Abstract: PDF file - 108K, Regression estimates for associations between density measures and risk factors in the SIBS cohort.
Published: 2023

16. Data from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter
Abstract: Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist–hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls.Methods: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable.Results: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10−17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89–2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44–1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10–1.39; P = 5.3 × 10−4). There was evidence of directional pleiotropy (P = 1.5 × 10−4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10−4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS.Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI.Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503–10. ©2016 AACR.
Published: 2023

17. Supplementary Tables 1 - 4 from Common Breast Cancer Susceptibility Variants in LSP1 and RAD51L1 Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk

Author: Isabel dos-Santos-Silva, John L. Hopper, V. Shane Pankratz, Anna H. Wu, Tina Audley, Kamila Czene, Louise Eriksson, JianJun Liu, Edyta Reszka, Agnieszka Bukowska, Beata Peplonska, Ewa Wesolowska, Jolanta Lissowska, Jonine D. Figuero, Norman F. Boyd, Julia A. Knight, Irene L. Andrulis, David J. Hunter, Susan E. Hankinson, Sara Lindström, Anne-Lise Børresen-Dale, Vessela N. Kristensen, Inger Torhild Gram, Grethe I.G. Alnaes, Margarethe Biong, Valeria A. McCormack, Nichola Johnson, Kate Walker, Christopher A. Haiman, Gertraud Maskarinec, Christy Woolcott, Laurence N. Kolonel, Loic Le Marchand, Melissa C. Southey, Kavitha Krishnan, Laura Baglietto, Graham G. Giles, Fergus J. Couch, Gek Kwan-Lim, Martin O. Leach, Rosalind A. Eeles, Susan J. Ramus, Simon A. Gayther, Eunjung Lee, Giske Ursin, Kay-Tee Khaw, Ruth J.F. Loos, Nicholas J. Wareham, Ruth M.L. Warren, Robert N. Luben, Deborah J. Thompson, Douglas F. Easton, Jajini S. Varghese, Jean Leyland, Judith Brown, Petra H.M. Peeters, N. Charlotte Onland-Moret, Mariëtte Lokate, Carla H. van Gils, Javier Benitez, Anna Gonzalez-Neira, Pablo Fernández-Navarro, Marina Pollan, Matthias W. Beckmann, Katharina Heusinger, Sebastian M. Jud, Gretchen L. Gierach, Fabrice Odefrey, Carmel Apicella, Jennifer Stone, Jingmei Li, Rulla M. Tamimi, Per Hall, Peter A. Fasching, Christopher G. Scott, and Celine M. Vachon
Abstract: PDF file, 120KB, Supplemental Table 1. Study Descriptions, Design and Sample Size for 19 DENSNP Studies. Caucasian Women Only. Supplemental Table 2. Source and Timing of Reproductive and Anthropometric Variable Collection. Supplemental Table 3. Description of Mammogram View, Side, Film Digitizer and Density Estimation Software for DENSNP Studies. Supplemental Table 4. Genotyping Platform and SNP Call Rates Performed by Each Study.
Published: 2023

18. Supplemental Table 1. Details of cases and controls included in the endometrial cancer analyses from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter
Abstract: Excel file detailing case-control populations
Published: 2023

19. Supplemental Table 2. Average BMIs in the ANECS, SEARCH and iCOGS endometrial cancer datasets. from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter
Abstract: Excel file detailing average BMI per study population
Published: 2023

20. Supplementary Table 5 from Common Breast Cancer Susceptibility Variants in LSP1 and RAD51L1 Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk

Author: Isabel dos-Santos-Silva, John L. Hopper, V. Shane Pankratz, Anna H. Wu, Tina Audley, Kamila Czene, Louise Eriksson, JianJun Liu, Edyta Reszka, Agnieszka Bukowska, Beata Peplonska, Ewa Wesolowska, Jolanta Lissowska, Jonine D. Figuero, Norman F. Boyd, Julia A. Knight, Irene L. Andrulis, David J. Hunter, Susan E. Hankinson, Sara Lindström, Anne-Lise Børresen-Dale, Vessela N. Kristensen, Inger Torhild Gram, Grethe I.G. Alnaes, Margarethe Biong, Valeria A. McCormack, Nichola Johnson, Kate Walker, Christopher A. Haiman, Gertraud Maskarinec, Christy Woolcott, Laurence N. Kolonel, Loic Le Marchand, Melissa C. Southey, Kavitha Krishnan, Laura Baglietto, Graham G. Giles, Fergus J. Couch, Gek Kwan-Lim, Martin O. Leach, Rosalind A. Eeles, Susan J. Ramus, Simon A. Gayther, Eunjung Lee, Giske Ursin, Kay-Tee Khaw, Ruth J.F. Loos, Nicholas J. Wareham, Ruth M.L. Warren, Robert N. Luben, Deborah J. Thompson, Douglas F. Easton, Jajini S. Varghese, Jean Leyland, Judith Brown, Petra H.M. Peeters, N. Charlotte Onland-Moret, Mariëtte Lokate, Carla H. van Gils, Javier Benitez, Anna Gonzalez-Neira, Pablo Fernández-Navarro, Marina Pollan, Matthias W. Beckmann, Katharina Heusinger, Sebastian M. Jud, Gretchen L. Gierach, Fabrice Odefrey, Carmel Apicella, Jennifer Stone, Jingmei Li, Rulla M. Tamimi, Per Hall, Peter A. Fasching, Christopher G. Scott, and Celine M. Vachon
Abstract: PDF file, 20KB, Supplemental Table 5a. Associations of Common Breast Cancer Susceptibility Variants with Adjusted Percent Mammographic Density. Supplemental Table 5b. Associations of Common Breast Cancer Susceptibility Variants with Adjusted Mammographic Dense Area. Supplemental Table 5c. Associations of Common Breast Cancer Susceptibility Variants with Adjusted Mammographic Non Dense Area.
Published: 2023

21. Supplementary Table 3: Association of 77 body mass index (BMI) SNPs with endometrial cancer risk and BMI in the endometrial cancer dataset from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter
Abstract: Excel file detailing single BMI SNP associations with EC risk and BMI
Published: 2023

22. Supplementary Table 6 from Common Breast Cancer Susceptibility Variants in LSP1 and RAD51L1 Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk

Author: Isabel dos-Santos-Silva, John L. Hopper, V. Shane Pankratz, Anna H. Wu, Tina Audley, Kamila Czene, Louise Eriksson, JianJun Liu, Edyta Reszka, Agnieszka Bukowska, Beata Peplonska, Ewa Wesolowska, Jolanta Lissowska, Jonine D. Figuero, Norman F. Boyd, Julia A. Knight, Irene L. Andrulis, David J. Hunter, Susan E. Hankinson, Sara Lindström, Anne-Lise Børresen-Dale, Vessela N. Kristensen, Inger Torhild Gram, Grethe I.G. Alnaes, Margarethe Biong, Valeria A. McCormack, Nichola Johnson, Kate Walker, Christopher A. Haiman, Gertraud Maskarinec, Christy Woolcott, Laurence N. Kolonel, Loic Le Marchand, Melissa C. Southey, Kavitha Krishnan, Laura Baglietto, Graham G. Giles, Fergus J. Couch, Gek Kwan-Lim, Martin O. Leach, Rosalind A. Eeles, Susan J. Ramus, Simon A. Gayther, Eunjung Lee, Giske Ursin, Kay-Tee Khaw, Ruth J.F. Loos, Nicholas J. Wareham, Ruth M.L. Warren, Robert N. Luben, Deborah J. Thompson, Douglas F. Easton, Jajini S. Varghese, Jean Leyland, Judith Brown, Petra H.M. Peeters, N. Charlotte Onland-Moret, Mariëtte Lokate, Carla H. van Gils, Javier Benitez, Anna Gonzalez-Neira, Pablo Fernández-Navarro, Marina Pollan, Matthias W. Beckmann, Katharina Heusinger, Sebastian M. Jud, Gretchen L. Gierach, Fabrice Odefrey, Carmel Apicella, Jennifer Stone, Jingmei Li, Rulla M. Tamimi, Per Hall, Peter A. Fasching, Christopher G. Scott, and Celine M. Vachon
Abstract: PDF file, 133KB, Supplemental Table 6a. Per-Allele Association (SE) of Breast Cancer Susceptibility Variants with Mammographic Percent Density Stratifying by Case Status, BMI, Menopausal Status and PMH Use. Supplemental Table 6b. Per-Allele Associations (SE) of Breast Cancer Susceptibility Variants with Adjusted Mammographic Dense Area Stratifying by Case Status, BMI Menopausal Status and PMH Use. Supplemental Table 6c. Per-Allele Associations (SE) of Breast Cancer Susceptibility Variants with Adjusted Mammographic Non Dense Area Stratifying by Case Status, BMI Menopausal Status and PMH Use.
Published: 2023

23. Data from The Heritability of Mammographic Breast Density and Circulating Sex-Hormone Levels: Two Independent Breast Cancer Risk Factors

Author: Deborah J. Thompson, Douglas F. Easton, Mitchell Dowsett, Ruth M.L. Warren, Tina Audley, Jean Leyland, Judith Brown, Elizabeth Folkerd, Paula L. Smith, and Jajini S. Varghese
Abstract: Background: Mammographic breast density and endogenous sex-hormone levels are both strong risk factors for breast cancer. This study investigated whether there is evidence for a shared genetic basis between these risk factors.Methods: Using data on 1,286 women from 617 families, we estimated the heritabilities of serum estradiol, testosterone, and sex-hormone binding globulin (SHBG) levels and of three measures of breast density (dense area, nondense area, and percentage density). We tested for associations between hormone levels and density measures and estimated the genetic and environmental correlations between pairs of traits using variance and covariance components models and pedigree-based maximum likelihood methods.Results: We found no significant associations between estradiol, testosterone, or SHBG levels and any of the three density measures, after adjusting for body mass index (BMI).The estimated heritabilities were 63%, 66%, and 65% for square root–transformed adjusted percentage density, dense area, and nondense area, respectively, and 40%, 25%, and 58% for log-transformed–adjusted estradiol, testosterone, and SHBG. We found no evidence of a shared genetic basis between any hormone levels and any measure of density, after adjusting for BMI. The negative genetic correlation between dense and nondense areas remained significant even after adjustment for BMI and other covariates (ρ = −0.34; SE = 0.08; P = 0.0005).Conclusions: Breast density and sex hormones can be considered as independent sets of traits.Impact: Breast density and sex hormones can be used as intermediate phenotypes in the search for breast cancer susceptibility loci. Cancer Epidemiol Biomarkers Prev; 21(12); 2167–75. ©2012 AACR.
Published: 2023

24. Supplementary Table 4. Association of 47 waist-hip ratio (WHR) SNPs with endometrial cancer risk from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter
Abstract: Excel file detailing single WHR SNP associations with EC risk
Published: 2023

25. Data from Common Breast Cancer Susceptibility Variants in LSP1 and RAD51L1 Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk

Author: Isabel dos-Santos-Silva, John L. Hopper, V. Shane Pankratz, Anna H. Wu, Tina Audley, Kamila Czene, Louise Eriksson, JianJun Liu, Edyta Reszka, Agnieszka Bukowska, Beata Peplonska, Ewa Wesolowska, Jolanta Lissowska, Jonine D. Figuero, Norman F. Boyd, Julia A. Knight, Irene L. Andrulis, David J. Hunter, Susan E. Hankinson, Sara Lindström, Anne-Lise Børresen-Dale, Vessela N. Kristensen, Inger Torhild Gram, Grethe I.G. Alnaes, Margarethe Biong, Valeria A. McCormack, Nichola Johnson, Kate Walker, Christopher A. Haiman, Gertraud Maskarinec, Christy Woolcott, Laurence N. Kolonel, Loic Le Marchand, Melissa C. Southey, Kavitha Krishnan, Laura Baglietto, Graham G. Giles, Fergus J. Couch, Gek Kwan-Lim, Martin O. Leach, Rosalind A. Eeles, Susan J. Ramus, Simon A. Gayther, Eunjung Lee, Giske Ursin, Kay-Tee Khaw, Ruth J.F. Loos, Nicholas J. Wareham, Ruth M.L. Warren, Robert N. Luben, Deborah J. Thompson, Douglas F. Easton, Jajini S. Varghese, Jean Leyland, Judith Brown, Petra H.M. Peeters, N. Charlotte Onland-Moret, Mariëtte Lokate, Carla H. van Gils, Javier Benitez, Anna Gonzalez-Neira, Pablo Fernández-Navarro, Marina Pollan, Matthias W. Beckmann, Katharina Heusinger, Sebastian M. Jud, Gretchen L. Gierach, Fabrice Odefrey, Carmel Apicella, Jennifer Stone, Jingmei Li, Rulla M. Tamimi, Per Hall, Peter A. Fasching, Christopher G. Scott, and Celine M. Vachon
Abstract: Background: Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biologic mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to interindividual differences in mammographic density measures.Methods: We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and nondense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, BMI, and menopausal status.Results: Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (P = 0.00005) and adjusted percent density (P = 0.001), whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (P = 0.003), but not with adjusted dense area (P = 0.07).Conclusion: We identified two common breast cancer susceptibility variants associated with mammographic measures of radiodense tissue in the breast gland.Impact: We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association. Cancer Epidemiol Biomarkers Prev; 21(7); 1156–. ©2012 AACR.
Published: 2023

26. Supplementary Table 2 from The Heritability of Mammographic Breast Density and Circulating Sex-Hormone Levels: Two Independent Breast Cancer Risk Factors

Author: Deborah J. Thompson, Douglas F. Easton, Mitchell Dowsett, Ruth M.L. Warren, Tina Audley, Jean Leyland, Judith Brown, Elizabeth Folkerd, Paula L. Smith, and Jajini S. Varghese
Abstract: PDF file - 109K, Regression estimates for associations between sex-hormone measures and risk factors in the SIBS cohort.
Published: 2023

27. Supplementary Methods and Tables from The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers

Author: Douglas F. Easton, Jacques Simard, Stephen J. Chanock, Georgia Chenevix-Trench, Paul D.P. Pharoah, Antonis C. Antoniou, Daniela Seminara, Elizabeth Gillanders, Michael F. Seldin, Rosalind A. Eeles, Ulrike Peters, Ali Amin Al Olama, Jonathan Marchini, Rayjean J. Hung, Laura Ottini, Rita Schmutzler, Mads Thomassen, Kenneth Offit, Sue K. Park, John K. Field, Jack A. Taylor, Christopher K. Edlund, Tameka Shelford, Stephanie L. Schmit, Sylvie Laboissiere, Andrew Berchuck, Sune F. Nielsen, Marc T. Goodman, Deborah J. Thompson, Yongyong Shi, Hongbing Shen, Tracy A. O'Mara, Marjorie Riggan, Paul Brennan, Linda E. Kelemen, Sara Benlloch, Catherine M. Phelan, James D. McKay, Marcia Adams, Sara Lindström, Liesel FitzGerald, Peter Kraft, Zsofia Kote-Jarai, Katja Butterbach, Julie M. Cunningham, Judith Manz, Penny Soucy, Karoline Kuchenbaecker, Andrew Lee, Lesley McGuffog, Hua Ling, Belynda D. Hicks, Irene Brüske-Hohlfeld, Melanie Waldenberger, Angela Risch, Heike Bickeböller, David V. Conti, Graham G. Giles, Judith L. Forman, Fergus J. Couch, David E. Goldgar, Stephen Demetriades, Stefanie Nelson, David J. Van Den Berg, François Bacot, Daniel Vincent, Daniel Tessier, Craig Luccarini, Ahsan Kamal, Christopher A. Haiman, Charlisse Caga-Anan, Stig E. Bojesen, Dennis J. Hazelett, Gerhard A. Coetzee, Elizabeth Pugh, Jane Romm, Xiangjun Xiao, Yafang Li, Amanda B. Spurdle, Kimberly Doheny, Laura Fachal, Kyriaki Michailidou, Alison M. Dunning, Stephen B. Gruber, Thomas A. Sellers, David J. Hunter, Graham Casey, Simon A. Gayther, Fredrick R. Schumacher, Jinyoung Byun, Zhaoming Wang, Joe Dennis, and Christopher I. Amos
Abstract: Supplementary Methods and Tables
Published: 2023

28. Supplementary Text for: Genetic risk score Mendelian randomization shows that obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter
Abstract: Supplementary Text for manuscript.
Published: 2023

29. Data from The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers

Author: Douglas F. Easton, Jacques Simard, Stephen J. Chanock, Georgia Chenevix-Trench, Paul D.P. Pharoah, Antonis C. Antoniou, Daniela Seminara, Elizabeth Gillanders, Michael F. Seldin, Rosalind A. Eeles, Ulrike Peters, Ali Amin Al Olama, Jonathan Marchini, Rayjean J. Hung, Laura Ottini, Rita Schmutzler, Mads Thomassen, Kenneth Offit, Sue K. Park, John K. Field, Jack A. Taylor, Christopher K. Edlund, Tameka Shelford, Stephanie L. Schmit, Sylvie Laboissiere, Andrew Berchuck, Sune F. Nielsen, Marc T. Goodman, Deborah J. Thompson, Yongyong Shi, Hongbing Shen, Tracy A. O'Mara, Marjorie Riggan, Paul Brennan, Linda E. Kelemen, Sara Benlloch, Catherine M. Phelan, James D. McKay, Marcia Adams, Sara Lindström, Liesel FitzGerald, Peter Kraft, Zsofia Kote-Jarai, Katja Butterbach, Julie M. Cunningham, Judith Manz, Penny Soucy, Karoline Kuchenbaecker, Andrew Lee, Lesley McGuffog, Hua Ling, Belynda D. Hicks, Irene Brüske-Hohlfeld, Melanie Waldenberger, Angela Risch, Heike Bickeböller, David V. Conti, Graham G. Giles, Judith L. Forman, Fergus J. Couch, David E. Goldgar, Stephen Demetriades, Stefanie Nelson, David J. Van Den Berg, François Bacot, Daniel Vincent, Daniel Tessier, Craig Luccarini, Ahsan Kamal, Christopher A. Haiman, Charlisse Caga-Anan, Stig E. Bojesen, Dennis J. Hazelett, Gerhard A. Coetzee, Elizabeth Pugh, Jane Romm, Xiangjun Xiao, Yafang Li, Amanda B. Spurdle, Kimberly Doheny, Laura Fachal, Kyriaki Michailidou, Alison M. Dunning, Stephen B. Gruber, Thomas A. Sellers, David J. Hunter, Graham Casey, Simon A. Gayther, Fredrick R. Schumacher, Jinyoung Byun, Zhaoming Wang, Joe Dennis, and Christopher I. Amos
Abstract: Background: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers, and cancer-related traits.Methods: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers, and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background.Results: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis.Conclusions: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine-mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental, and lifestyle-related exposures.Impact: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. Cancer Epidemiol Biomarkers Prev; 26(1); 126–35. ©2016 AACR.
Published: 2023

30. Supplementary Table 2 from Novel Associations between Common Breast Cancer Susceptibility Variants and Risk-Predicting Mammographic Density Measures

Author: Celine M. Vachon, John L. Hopper, V. Shane Pankratz, Peter A. Fasching, Douglas F. Easton, Alison M. Dunning, Paul Pharoah, Jacques Simard, Joe Dennis, Kyriaki Michailidou, Qin Wang, Manjeet K. Bolla, Inger Torhild Gram, Anne-Lise Borresen-Dale, Vessela N. Kristensen, Grethe I. Grenaker Alnaes, Giske Ursin, Julia A. Knight, Irene L. Andrulis, Carmel Apicella, Melissa C. Southey, Kavitha Krishnan, Laura Baglietto, Graham G. Giles, Christopher Haiman, Gertraud Maskarinec, Christy Woolcott, Laurence N. Kolonel, Loic Le Marchand, Mark A. Helvie, Heang-Ping Chan, Kaanan P. Shah, Julie A. Douglas, Matthias W. Beckmann, Katharina Heusinger, Sebastian M. Jud, Nicholas J. Wareham, Paula Smith, Kay-Tee Khaw, Robert N. Luben, Ruth M.L. Warren, Jean Leyland, Judith Brown, Fergus J. Couch, Kristen Purrington, Janet E. Olson, Julie Cunningham, Matt Jensen, Per Hall, Kamila Czene, Louise Eriksson, Jingmei Li, Aditi Hazra, Peter Kraft, Sara Lindstrom, Rulla M. Tamimi, Christopher Scott, Isabel dos Santos Silva, Deborah J. Thompson, and Jennifer Stone
Abstract: Supplementary Table 2. Associations (95% Confidence Interval (CI) in brackets) between all 77 breast cancer susceptibility variants and percent dense area, dense area, and non-dense area
Published: 2023

31. Supplementary Figure 1 from Mammographic Breast Density and Breast Cancer: Evidence of a Shared Genetic Basis

Author: Douglas F. Easton, Nazneen Rahman, Rulla M. Tamimi, John L. Hopper, Per Hall, Norman F. Boyd, Kamila Czene, Louise Eriksson, Jingmei Li, Jennifer Stone, Melissa C. Southey, Carmel Apicella, Fergus J. Couch, Elizabeth J. Atkinson, Christopher G. Scott, Celine M. Vachon, Lisa J. Martin, Andrew D. Paterson, Johanna Rommens, Nicholas J. Wareham, Ruth J. Loos, Robert N. Luben, Ruth M.L. Warren, Jean Leyland, Judith Brown, Clare Turnbull, Sara Lindström, Kyriaki Michailidou, Deborah J. Thompson, and Jajini S. Varghese
Abstract: PDF file - 275K, Significance of the mammographic breast density polygenic risk score (PRS) for the prediction of breast cancer risk, according to percent cut-off of SNPs used in the PRS: sensitivity analysis using imputed case:control genotype dosages.
Published: 2023

32. Supplementary Table 3 from Novel Associations between Common Breast Cancer Susceptibility Variants and Risk-Predicting Mammographic Density Measures

Author: Celine M. Vachon, John L. Hopper, V. Shane Pankratz, Peter A. Fasching, Douglas F. Easton, Alison M. Dunning, Paul Pharoah, Jacques Simard, Joe Dennis, Kyriaki Michailidou, Qin Wang, Manjeet K. Bolla, Inger Torhild Gram, Anne-Lise Borresen-Dale, Vessela N. Kristensen, Grethe I. Grenaker Alnaes, Giske Ursin, Julia A. Knight, Irene L. Andrulis, Carmel Apicella, Melissa C. Southey, Kavitha Krishnan, Laura Baglietto, Graham G. Giles, Christopher Haiman, Gertraud Maskarinec, Christy Woolcott, Laurence N. Kolonel, Loic Le Marchand, Mark A. Helvie, Heang-Ping Chan, Kaanan P. Shah, Julie A. Douglas, Matthias W. Beckmann, Katharina Heusinger, Sebastian M. Jud, Nicholas J. Wareham, Paula Smith, Kay-Tee Khaw, Robert N. Luben, Ruth M.L. Warren, Jean Leyland, Judith Brown, Fergus J. Couch, Kristen Purrington, Janet E. Olson, Julie Cunningham, Matt Jensen, Per Hall, Kamila Czene, Louise Eriksson, Jingmei Li, Aditi Hazra, Peter Kraft, Sara Lindstrom, Rulla M. Tamimi, Christopher Scott, Isabel dos Santos Silva, Deborah J. Thompson, and Jennifer Stone
Abstract: Supplementary Table 3. Associations (95% Confidence Interval (CI) in brackets) between breast cancer susceptibility variants and the mammographic measures with adjustment for case-control status
Published: 2023

33. Supplementary Table 1 from Novel Associations between Common Breast Cancer Susceptibility Variants and Risk-Predicting Mammographic Density Measures

Author: Celine M. Vachon, John L. Hopper, V. Shane Pankratz, Peter A. Fasching, Douglas F. Easton, Alison M. Dunning, Paul Pharoah, Jacques Simard, Joe Dennis, Kyriaki Michailidou, Qin Wang, Manjeet K. Bolla, Inger Torhild Gram, Anne-Lise Borresen-Dale, Vessela N. Kristensen, Grethe I. Grenaker Alnaes, Giske Ursin, Julia A. Knight, Irene L. Andrulis, Carmel Apicella, Melissa C. Southey, Kavitha Krishnan, Laura Baglietto, Graham G. Giles, Christopher Haiman, Gertraud Maskarinec, Christy Woolcott, Laurence N. Kolonel, Loic Le Marchand, Mark A. Helvie, Heang-Ping Chan, Kaanan P. Shah, Julie A. Douglas, Matthias W. Beckmann, Katharina Heusinger, Sebastian M. Jud, Nicholas J. Wareham, Paula Smith, Kay-Tee Khaw, Robert N. Luben, Ruth M.L. Warren, Jean Leyland, Judith Brown, Fergus J. Couch, Kristen Purrington, Janet E. Olson, Julie Cunningham, Matt Jensen, Per Hall, Kamila Czene, Louise Eriksson, Jingmei Li, Aditi Hazra, Peter Kraft, Sara Lindstrom, Rulla M. Tamimi, Christopher Scott, Isabel dos Santos Silva, Deborah J. Thompson, and Jennifer Stone
Abstract: Supplementary Table 1. Mean (95% Confidence Interval (CI)) mammographic density measurements by covariate distribution
Published: 2023

34. Genetic insights into biological mechanisms governing human ovarian ageing

Author: Unnur Styrkarsdottir, Lynda M. Rose, Rehannah Borup, Anne B. Newman, Georgia Chenevix-Trench, Chikashi Terao, Jeremy A. Daniel, Christa Meisinger, Albert V. Smith, Emil Peter Thrane Hertz, Raymond Noordam, Wei He, Jennifer A. Smith, Mikael Eriksson, Konstantin Strauch, Daniel I. Chasman, Nicholas J. Timpson, Melissa A. Troester, Claudia Langenberg, Montserrat Garcia-Closas, Mohammad Arfan Ikram, Sara Lindström, Gad Rennert, Pascal Guénel, Kristina W. Olsen, Pierre Fontanillas, Ozren Polasek, Daniel F. Gudbjartsson, Frank B. Hu, Archie Campbell, Celine M. Vachon, Sheila Ulivi, Robin N Beaumont, Robert Karlsson, Lenore J. Launer, Renée de Mutsert, Annette Peters, David Schlessinger, Stefania Bandinelli, Rico Rueedi, Joop S.E. Laven, Pascal Timshel, Joanne M. Murabito, Kuang Lin, Jazib Hussain, Dennis O. Mook-Kanamori, Manjeet K. Bolla, Catherine E. Aiken, Javier Martin Gonzalez, Simon S. Cross, Immaculata De Vivo, Paul M. Ridker, Christopher A. Haiman, Gerardo Heiss, Jessica Tyrrell, Paul R. H. J. Timmers, Hironori Abe, Mike A. Nalls, Luigi Ferrucci, Natalia Perjakova, Jouke J. Hottenga, Robin G. Walters, Reedik Mägi, Niclas Håkansson, Miriam Dwek, Barbara McKnight, Sandra Turon, Stasa Stankovic, Linda Broer, Stephen J. Chanock, Martina La Bianca, Jenny Chang-Claude, Loic Le Marchand, Hamdi Mbarek, Doris Stöckl, Andrew F. Olshan, Graham G. Giles, James F. Wilson, Micaella Joaquim, Amruta Shrikhande, Eva Hoffmann, Stefania Benonisdottir, Ana Martínez-Marchal, Anthony J. Swerdlow, David Karasik, Nicholas J. Wareham, Peter A. Fasching, Jane L. Tarry-Adkins, Charles Kooperberg, Peter Vollenweider, Douglas F. Easton, Paula Aguilera, Jessica D. Faul, Patrik K. E. Magnusson, Emmanouil Saloustros, Alpa V. Patel, Ellen W. Demerath, Qin Wang, Aditya Sankar, Christopher G. Scott, Iffat Rahman, Sharon L.R. Kardia, Peter K. Joshi, Caterina Barbieri, Claus Yding Andersen, Tõnu Esko, Massimo Mezzavilla, Nicholas G. Martin, Rebecca D. Jackson, Alison D. Murray, Marina Ciullo, Nicholas Bowker, Anna Murray, Patrick Deelen, Zoltán Kutalik, Alicja Wolk, Manuela Gago-Dominguez, Eleonora Porcu, Laura Crisponi, Michela Traglia, Katharina E. Schraut, Antonietta Robino, Chunyan He, Bruce H. R. Wolffenbuttel, Henry Völzke, Daniela Ruggiero, John R. B. Perry, Lude Franke, Igor Rudan, Angela Cox, Unnur Þorsteinsdottir, Christian Gieger, David R. Weir, Jodie N. Painter, Martha S. Linet, Massimo Mangino, Melissa C. Southey, Petr Solc, Tim D. Spector, Christiana Kartsonaki, Momoko Horikoshi, Meir J. Stampfer, Eulalia Catamo, Mònica Ferrer-Roda, Ko Willems van Dijk, Daniela Toniolo, Caroline Hayward, Lili Milani, Chloé Sarnowski, Jian'an Luan, Behrooz Z. Alizadeh, Jenny A. Visser, Stig E. Bojesen, Genevieve Lachance, Ulrike Peters, Antonella Mulas, John J. Spinelli, Elnaz Naderi, Andrew R. Wood, Paul D.P. Pharoah, Elinor J. Sawyer, Annique Claringbould, Saleh Shekari, David G. Hunter, Marie Louise Grøndahl, Vilmundur Gudnason, Nora Franceschini, Dale P. Sandler, Dale R. Nyholt, Jacques E. Rossouw, Amber N. Wilcox, Thomas U. Ahearn, Hedy S. Rennert, Olivier B. Bakker, Jingmei Li, Francesco Cucca, Eric Boerwinkle, Matthias W. Beckmann, Cristina Menni, Minouk J. Schoemaker, Esther M. John, Tune H. Pers, Andrés J. López-Contreras, Tanguy Corre, Jonathan Marten, Alice M. Arnold, N. Charlotte Onland-Moret, Lucie Knoblochova, Anna Pujol, Kathryn L. Lunetta, Marjanka K. Schmidt, Teresa Nutile, Serena Sanna, Gonneke Willemsen, Roger L. Milne, Kristan J. Aronson, Frits R. Rosendaal, Murielle Bochud, Ken K. Ong, Susan M. Ring, Nancy L. Pedersen, Blair H. Smith, Ivana Kolcic, Annelie Augustinsson, Jose E. Castelao, Alexander Teumer, Felix R. Day, Sven Bergmann, Timothy M. Frayling, Lauren R. Teras, George Davey Smith, Thomas Meitinger, Alison M. Dunning, Ignasi Roig, Dorret I. Boomsma, Harald Grallert, Toshiko Tanaka, Katherine S. Ruth, Julie E. Buring, Marek Zygmunt, Uwe Völker, Irene L. Andrulis, Håkan Olsson, Harry Campbell, Cari M. Kitahara, Annika Lindblom, Yvonne T. van der Schouw, Cinzia Sala, Debbie A Lawlor, Joe Dennis, Yongmei Liu, Yan Huang, Stephen Burgess, Brumat Marco, Veronique Vitart, Kari Stefansson, Susan E. Ozanne, Kamila Czene, Simin Liu, John L. Hopper, Joyce B. J. van Meurs, Satoshi H. Namekawa, Miya Kudo Høffding, Fergus J. Couch, Ajuna Azad, Eco J. C. de Geus, Liming Li, Grant W. Montgomery, Peter Kraft, André G. Uitterlinden, Arto Mannermaa, Heiko Becher, Allison W. Kurian, Vallari Shukla, Zhengming Chen, Per Hall, Jennifer A. Brody, Rossella Sorice, Wei Zhao, Andres Metspalu, Sarah E. Medland, Tricia Lindstrom, Clarice R. Weinberg, Bruce M. Psaty, Thérèse Truong, Anna Marie Mulligan, Deborah J. Thompson, Patrick Sulem, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Hoffmann, Eva R [0000-0002-2588-0652], Murray, Anna [0000-0002-2351-2522], Roig, Ignasi [0000-0003-0313-3581], Perry, John RB [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Biological Psychology, APH - Mental Health, APH - Methodology, APH - Personalized Medicine, and APH - Health Behaviors & Chronic Diseases
Subjects: Gerontology, Aging, Far East, Endocrinology, Diabetes and Metabolism, Menopause, Premature, Genome-wide association study, VARIANTS, Primary Ovarian Insufficiency, Inbred C57BL, Bioinformatics, DISEASE, Healthy Aging, genetics of ovarian aging, Fragile X Mental Retardation Protein, Mice, Endocrinology, Medicine, EARLY MENOPAUSE, media_common, RISK, Multidisciplinary, Asia, Eastern, Reproduction, Longevity, Middle Aged, Europe, MENDELIAN RANDOMIZATION, Medical genetics, Female, ICEP, Menopause, Adult, Alleles, Animals, Bone and Bones, Checkpoint Kinase 1, Checkpoint Kinase 2, Diabetes Mellitus, Type 2, Diet, Fertility, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mice, Inbred C57BL, Ovary, Uterus, Type 2, medicine.medical_specialty, media_common.quotation_subject, MEDLINE, Biology, Premature ovarian insufficiency, Article, genome-wide meta-analysis, SDG 3 - Good Health and Well-being, GERMLINE, Diabetes Mellitus, Genetic predisposition, Ovarian reserve, Premature, business.industry, Human genetics, CHROMOSOME SYNAPSIS, DNA-DAMAGE, Ageing, EXPRESSION ANALYSIS, business, MEIOTIC CELL-CYCLE
Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.
Published: 2021

35. Genetic predisposition to mosaic Y chromosome loss in blood

Author: Ragnar P. Kristjansson, Steven A. McCarroll, Florian Zink, Malcolm G. Dunlop, Nicholas J. Wareham, Yoichiro Kamatani, Daniel F. Gudbjartsson, Giulio Genovese, Rong Li, Stephen J. Chanock, Unnur Thorsteinsdottir, Ben Kinnersley, Kari Stefansson, Philip J. Law, Martin Ingelsson, Lars Forsberg, Joe Dennis, Richard S. Houlston, Jonatan Halvardson, Nicola D. Kerrison, Chikashi Terao, Douglas F. Easton, Anna Murray, Yunxuan Jiang, Jan P. Dumanski, Chey Loveday, Steve P Jackson, Robert A. Scott, Edyta Rychlicka-Buniowska, Ian Tomlinson, Daniel J Wright, Deborah J. Thompson, Victoria A Fisher, Yoshinori Murakami, John R. B. Perry, Paweł Olszewski, Felix R. Day, Eva Hoffmann, Hanna Davies, Po-Ru Loh, Adam Auton, Siddhartha Kar, Behrooz Torabi Moghadam, Clare Turnbull, Ken K. Ong, Marcus Danielsson, Jacob C. Ulirsch, Jonas Mattisson, Patrick Sulem, Olafur B. Davidsson, Mitchell J. Machiela, Internal Medicine, APH - Methodology, APH - Mental Health, Biological Psychology, APH - Personalized Medicine, and APH - Health Behaviors & Chronic Diseases
Subjects: Male, 0301 basic medicine, Haematopoietic system, Genome-wide association study, Chromosomes, Human, Y/genetics, Genome-wide association studies, 0302 clinical medicine, Y Chromosome, Neoplasms, Databases, Genetic, Leukocytes, Cancer genomics, Genetics, Multidisciplinary, Mosaicism, Genetic Predisposition to Disease/genetics, Leukocytes/pathology, Middle Aged, Neoplasms/genetics, 3. Good health, 030220 oncology & carcinogenesis, Medical genetics, Female, Chromosome Deletion, Human, Genetic Markers, Adult, Genomic instability, medicine.medical_specialty, Cell division, Y/genetics, Biology, Y chromosome, Article, Genomic Instability, Chromosomes, Databases, 03 medical and health sciences, Genetic, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Gene, Aged, Genetic Markers/genetics, Chromosomes, Human, Y, Computational Biology, Cancer, Chromosome, medicine.disease, United Kingdom, 030104 developmental biology, Genetic marker, Genomic Instability/genetics
Abstract: Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1–5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases. A genome-wide association study of mosaic loss of chromosome Y (LOY) in UK Biobank participants identifies 156 genetic determinants of LOY, showing that LOY is associated with cancer and non-haematological health outcomes.
Published: 2019

36. Circulating vitamin D concentrations and risk of breast and prostate cancer: a Mendelian randomization study

Author: Graham G. Giles, Xia Jiang, Konstantinos K. Tsilidis, Deborah J. Thompson, Meir J. Stampfer, Wei Zheng, Edward Giovannucci, Peter Kraft, Richard M. Martin, Joellen M. Schildkraut, Marc J. Gunter, Kawthar Al-Dabhani, Timothy J. Key, Philip C Haycock, Shaneda N. Warren Andersen, Niki Dimou, Sarah J Lewis, Rosalind A. Eeles, Kenneth Muir, Brandon L. Pierce, and David E. Neal
Subjects: Male, 0301 basic medicine, Oncology, Epidemiology, Prostatic Neoplasms/epidemiology, Receptors, Estrogen/biosynthesis, Prostate cancer, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Prostate, Medicine, 030212 general & internal medicine, prostate, Breast Neoplasms/epidemiology, 0104 Statistics, Mendelian Randomization Analysis, General Medicine, Middle Aged, Causality, serum vitamin D concentrations, medicine.anatomical_structure, Vitamin D/blood, Female, ICEP, Vitamin, medicine.medical_specialty, PRACTICAL, CRUK, BPC3, CAPS and PEGASUS consortia, Polymorphism, Single Nucleotide, 1117 Public Health and Health Services, 03 medical and health sciences, Breast cancer, Internal medicine, Mendelian randomization, Vitamin D and neurology, Humans, breast, Aged, business.industry, Cancer, medicine.disease, 030104 developmental biology, chemistry, business, malignancy, Genome-Wide Association Study
Abstract: BackgroundObservational studies have suggested an association between circulating vitamin D concentrations [25(OH)D] and risk of breast and prostate cancer, which was not supported by a recent Mendelian randomization (MR) analysis comprising 15 748 breast and 22 898 prostate-cancer cases. Demonstrating causality has proven challenging and one common limitation of MR studies is insufficient power.MethodsWe aimed to determine whether circulating concentrations of vitamin D are causally associated with the risk of breast and prostate cancer, by using summary-level data from the largest ever genome-wide association studies conducted on vitamin D (N = 73 699), breast cancer (Ncase = 122 977) and prostate cancer (Ncase = 79 148). We constructed a stronger instrument using six common genetic variants (compared with the previous four variants) and applied several two-sample MR methods.ResultsWe found no evidence to support a causal association between 25(OH)D and risk of breast cancer [OR per 25 nmol/L increase, 1.02 (95% confidence interval: 0.97–1.08), P = 0.47], oestrogen receptor (ER)+ [1.00 (0.94–1.07), P = 0.99] or ER− [1.02 (0.90–1.16), P = 0.75] subsets, prostate cancer [1.00 (0.93–1.07), P = 0.99] or the advanced subtype [1.02 (0.90–1.16), P = 0.72] using the inverse-variance-weighted method. Sensitivity analyses did not reveal any sign of directional pleiotropy.ConclusionsDespite its almost five-fold augmented sample size and substantially improved statistical power, our MR analysis does not support a causal effect of circulating 25(OH)D concentrations on breast- or prostate-cancer risk. However, we can still not exclude a modest or non-linear effect of vitamin D. Future studies may be designed to understand the effect of vitamin D in subpopulations with a profound deficiency.
Published: 2018

37. Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer

Author: Timothy H.T. Cheng, V. Wendy Setiawan, Jolanta Lissowska, Kamila Czene, Zhaoming Wang, Linda S. Cook, Shirley Hodgson, Mitul Shah, Matthias W. Beckmann, Douglas F. Easton, Annika Lindblom, Daniel D. Buchanan, Wei Zheng, Constance Turman, Gloria E. Sarto, Susan E. Hankinson, Chu Chen, Joe Dennis, Christine M. Friedenreich, Dylan M. Glubb, Peter Hillemanns, Tracy A. O'Mara, Camilla Krakstad, Yong-Bing Xiang, Arif B. Ekici, Maxine M. Chen, Marta Crous-Bous, Montserrat Garcia-Closas, David Van Den Berg, Amanda Black, Immaculata De Vivo, Roger L. Milne, Geoffrey Otton, Frédéric Amant, Timothy R. Rebbeck, Carlotta Sacerdote, Erling A. Hoivik, Xiao-Ou Shu, Melissa C. Southey, Paul L. Auer, Brooke L. Fridley, Thilo Dörk, Elizabeth G. Holliday, Fredrick R. Schumacher, Loreall Pooler, Daniela Annibali, Mia M. Gaudet, Maggie Gorman, Peter A. Fasching, Matthias Rübner, Hannah P. Yang, Graham G. Giles, Stefan P. Renner, Jirong Long, Ellen L. Goode, Katie A. Ashton, Claire Palles, Emma Tham, Diether Lambrechts, Xin Sheng, Rodney J. Scott, Angela M. Jones, Alexander Hein, Amanda B. Spurdle, Nicolas Wentzensen, David J. Hunter, Rami Nassir, Peter Kraft, Lynn Martin, Christopher A. Haiman, Alison M. Dunning, Stephen J. Chanock, Jone Trovik, Loic Le Marchand, Harvey A. Risch, Tony Proietto, Matthias Dürst, Sean C. Dowdy, Lucy Xia, Miriam Mints, Anthony M. Magliocco, Pik Fang Kho, Herbert Yu, Lingeng Lu, Mark McEvoy, Xiaolin Liang, Louise A. Brinton, Per Hall, Jonathan Tyrer, Ingo B. Runnebaum, Penelope M. Webb, John Attia, Ian Tomlinson, Deborah J. Thompson, Buchanan, Daniel D [0000-0003-2225-6675], Chen, Chu [0000-0003-2267-8050], De Vivo, Immaculata [0000-0002-7185-7402], Dörk, Thilo [0000-0002-9458-0282], Fasching, Peter A [0000-0003-4885-8471], Friedenreich, Christine M [0000-0002-4783-1966], Gaudet, Mia M [0000-0002-6429-4007], Goode, Ellen L [0000-0002-9094-8326], Lu, Lingeng [0000-0001-9871-0809], Sacerdote, Carlotta [0000-0002-8008-5096], Shu, Xiao-Ou [0000-0002-0711-8314], Wang, Zhaoming [0000-0001-7556-3869], Wentzensen, Nicolas [0000-0003-1251-0836], Xiang, Yong-Bing [0000-0002-3840-9915], Yu, Herbert [0000-0003-3950-4815], Spurdle, Amanda B [0000-0003-1337-7897], O'Mara, Tracy A [0000-0002-5436-3232], Apollo - University of Cambridge Repository, ARD - Amsterdam Reproduction and Development, Obstetrics and Gynaecology, and CCA - Imaging and biomarkers
Subjects: Oncology, Cancer Research, Colorectal cancer, Blood lipids, chemistry.chemical_compound, 0302 clinical medicine, HDL cholesterol, Medicine, triglycerides, METABOLIC SYNDROME, 2. Zero hunger, Mendelian Randomization Analysis, ASSOCIATION, 3. Good health, 030220 oncology & carcinogenesis, LDL cholesterol, SERUM-LIPIDS, Female, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, Risk, medicine.medical_specialty, endometrial cancer risk, Article, 03 medical and health sciences, INFLAMMATION, Internal medicine, Mendelian randomization, CAUSAL, Humans, Science & Technology, Cholesterol, business.industry, Endometrial cancer, Cholesterol, HDL, Case-control study, Cholesterol, LDL, medicine.disease, Endometrial Neoplasms, BODY-MASS INDEX, LIPOPROTEIN, chemistry, Case-Control Studies, RISK-FACTORS, Metabolic syndrome, business, Genome-Wide Association Study
Abstract: Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P
Published: 2021

38. Genetic insights into the biological mechanisms governing human ovarian ageing

Author: Unnur Styrkarsdottir, Daniel I. Chasman, Rehannah Borup, Anne B. Newman, Kristina W. Olsen, Lude Franke, Stefania Bandinelli, Nora Franceschini, Celine M. Vachon, Nicholas J. Timpson, James F. Wilson, Micaella Joaquim, Christa Meisinger, Felix R. Day, Charles Kooperberg, Qin Wang, Pascal Timshel, Dennis O. Mook-Kanamori, Luigi Ferrucci, Jennifer A. Smith, Miriam Dwek, Pascal Guénel, Claus Yding Andersen, Peter A. Fasching, Sven Bergmann, Thomas Meitinger, Nicholas Bowker, Jane L. Tarry-Adkins, Jeremy A. Daniel, Katharina E. Schraut, Mikael Eriksson, Amruta Shrikhande, Jacques E. Rossouw, Amber N. Wilcox, Simon S. Cross, Stasa Stankovic, Montserrat Garcia-Closas, Mohammad Arfan Ikram, Annette Peters, David Schlessinger, Sheila Ulivi, Mònica Ferrer-Roda, Immaculata De Vivo, Michela Traglia, Jessica Tyrrell, Paul R. H. J. Timmers, Rico Rueedi, Ko Willems van Dijk, N. Charlotte Onland-Moret, Doris Stöckl, Anthony J. Swerdlow, Paul M. Ridker, Zoltán Kutalik, Patrick Deelen, Gerardo Heiss, Marie Louise Grøndahl, Alison M. Dunning, Dale R. Nyholt, Nicholas J. Wareham, Reedik Mägi, Stephen J. Chanock, Martina La Bianca, Ozren Polasek, Daniel F. Gudbjartsson, Rebecca D. Jackson, Alison D. Murray, Lynda M. Rose, Hironori Abe, Joanne M. Murabito, Henry Völzke, Daniela Ruggiero, Dorret I. Boomsma, Harald Grallert, Stefania Benonisdottir, Javier Martin Gonzalez, Esther M. John, Natalia Perjakova, Georgia Chenevix-Trench, John R. B. Perry, Jenny Chang-Claude, Archie Campbell, Teresa Nutile, Ellen W. Demerath, Robin N Beaumont, Jouke J. Hottenga, Albert V. Smith, David Karasik, Linda Broer, Raymond Noordam, Wei He, Niclas Håkansson, Catherine E. Aiken, Robert Karlsson, Christopher A. Haiman, Massimo Mangino, Melissa C. Southey, Sharon L.R. Kardia, Nicholas G. Martin, Jodie N. Painter, Peter K. Joshi, Gonneke Willemsen, Lenore J. Launer, Alicja Wolk, Konstantin Strauch, Stig E. Bojesen, Manjeet K. Bolla, Allison W. Kurian, Renée de Mutsert, Joop S.E. Laven, Antonella Mulas, Igor Rudan, Vallari Shukla, Kathyrn L Lunetta, Susan E. Ozanne, Loic Le Marchand, Jenny A. Visser, Gad Rennert, Jennifer A. Brody, Paul D.P. Pharoah, Tune H. Pers, Sara Lindström, Ignasi Roig, Angela Cox, Unnur Þorsteinsdottir, Graham G. Giles, Toshiko Tanaka, Eva Hoffmann, Melissa A. Troester, Claudia Langenberg, Serena Sanna, Julie E. Buring, Anna Pujol, Mike A. Nalls, Kamila Czene, Tõnu Esko, Jian'an Luan, Lili Milani, Iffat Rahman, Sarah E. Medland, Caterina Barbieri, Emil Peter Trane Hertz, Behrooz Z. Alizadeh, David G. Hunter, Sandra Turon, Antonietta Robino, Marina Ciullo, Barbara McKnight, Chunyan He, Bruce H. R. Wolffenbuttel, David R. Weir, Daniela Toniolo, Ulrike Peters, George Davey-Smith, Saleh Shekari, Caroline Hayward, Elinor J. Sawyer, Patrick Sulem, Simin Liu, Tanguy Corre, Susan M. Ring, Peter Kraft, Alexander Teumer, Marjanka K. Schmidt, André G. Uitterlinden, Arto Mannermaa, Kristan J. Aronson, Heiko Becher, John L. Hopper, Alpa V. Patel, Joyce B. J. van Meurs, kConFab Investigators, Hamdi Mbarek, Frits R. Rosendaal, Minouk J. Schoemaker, Satoshi H. Namekawa, Miya Kudo Høffding, Fergus J. Couch, Nancy L. Pedersen, Jessica D. Faul, Patrik K. E. Magnusson, Jingmei Li, Christopher G. Scott, Joe Dennis, Genevieve Lachance, Ajuna Azad, Yongmei Liu, Elnaz Naderi, Andrew R. Wood, Yan Huang, Anna Murray, Annique Claringbould, Stephen Burgess, Jose E. Castelao, Brumat Marco, Eco J. C. de Geus, Veronique Vitart, Ken K. Ong, Kari Stefansson, Blair H. Smith, Francesco Cucca, Grant W. Montgomery, Emmanouil Saloustros, Andrés J. López-Contreras, Jonathan Marten, Håkan Olsson, Dale P. Sandler, Alice M. Arnold, Ana Martínez-Marchal, Tim D. Spector, Chloé Sarnowski, John J. Spinelli, Vilmundur Gudnason, Frank B. Hu, Thomas U. Ahearn, Hedy S. Rennert, Olivier B. Bakker, Eric Boerwinkle, Matthias W. Beckmann, Jazib Hussain, Uwe Völker, Peter Vollenweider, Douglas F. Easton, Irene L. Andrulis, Harry Campbell, Manuela Gago-Dominguez, Cari M. Kitahara, Yvonne T. van der Schouw, Eleonora Porcu, Annika Lindblom, Martha S. Linet, Meir J. Stampfer, Eulalia Catamo, Roger L. Milne, Ivana Kolcic, Annelie Augustinsson, Cinzia Sala, Debbie A Lawlor, Cristina Menni, Timothy M. Frayling, Lauren R. Teras, Marek Zygmunt, Tricia Lindstrom, Clarice R. Weinberg, Bruce M. Psaty, Thérèse Truong, Anna Marie Mulligan, Deborah J. Thompson, Per Hall, Rossella Sorice, Wei Zhao, Andres Metspalu, Katherine S. Ruth, Andrew F. Olshan, Massimo Mezzavilla, Murielle Bochud, and Christian Gieger
Subjects: media_common.quotation_subject, Genetic predisposition, Longevity, Fertility, Disease, Biology, Premature ovarian insufficiency, Bioinformatics, Ovarian reserve, FMR1, Human genetics, media_common
Abstract: Reproductive longevity is critical for fertility and impacts healthy ageing in women, yet insights into the underlying biological mechanisms and treatments to preserve it are limited. Here, we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in ∼200,000 women of European ancestry. These common alleles influence clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenicFMR1premutations. Identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increase fertility and extend reproductive life in mice. Causal inference analyses using the identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. These findings provide insight into the mechanisms governing ovarian ageing, when they act across the life-course, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
Published: 2021

39. Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers

Author: Ana Osorio, Fiona Bruinsma, Andrew J. Li, Janine Senz, Stacey J. Winham, Michael E. Carney, Deborah J. Thompson, Xifeng Wu, Susan J. Ramus, Alicia A. Tone, Robert P. Edwards, Chu Chen, Daniel D. Buchanan, Rüdiger Klapdor, Diether Lambrechts, Anthony N. Karnezis, Ralf Bützow, Graham G. Giles, Jolanta Kupryjanczyk, James D. Brenton, Pamela J. Thompson, Joseph L. Kelley, Hui Cai, Dylan M. Glubb, Peter Hillemanns, Veronica Wendy Setiawan, Reidun K. Kopperud, Francesmary Modugno, Rodney J. Scott, Karen H. Lu, Andreas du Bois, Weiva Sieh, Clara Bodelon, Katharina Bischof, Sarah E. Ferguson, Ignace Vergote, Todd L. Edwards, Nadeem Siddiqui, Jennifer A. Doherty, Celeste Leigh Pearce, David G. Huntsman, Håkan Olsson, Ailith Ewing, Tjoung-Won Park-Simon, Harvey A. Risch, Taymaa May, Soo Hwang Teo, Elizabeth G. Holliday, Penelope M. Webb, Lukasz Michael Szafron, Alexander Hein, Martin Köbel, Marjorie J. Riggan, Madhuri Koti, Ahmad Alsulimani, Matthias W. Beckmann, Heli Nevanlinna, Domenico Palli, Melissa C. Larson, Emily White, Ingo B. Runnebaum, Robert A. Vierkant, Elza Khusnutdinova, Jolanta Lissowska, Andrew Berchuck, Rosalind Glasspool, Drakoulis Yannoukakos, Alison M. Dunning, Rosario Tumino, Mia M. Gaudet, Alice S. Whittemore, Anna Jakubowska, Marcus Q. Bernardini, Jennifer B. Permuth, Kunle Odunsi, Aleksandra Gentry-Maharaj, Florentia Fostira, Philipp Harter, Rebecca Sutphen, Sandra Orsulic, Beata Spiewankiewicz, Susanne K. Kjaer, Jessica N. McAlpine, Valerie McGuire, Julie M. Cunningham, Jeffrey Killeen, Christine M. Friedenreich, Estrid Høgdall, George Fountzilas, Michelle A.T. Hildebrandt, Katja K.H. Aben, Tomasz Huzarski, Frédéric Amant, Zhaoming Wang, James M. Flanagan, Timothy R. Rebbeck, Joseph H. Rothstein, Clemens Liebrich, Immaculata De Vivo, Linda Titus, Anna deFazio, Jan Gawełko, Irene Konstantopoulou, Adriaan Vanderstichele, Stephen J. Chanock, Jenny Lester, Amanda B. Spurdle, Allan Jensen, Claus Høgdall, Daniela Annibali, Amalia Mattiello, Peter Kraft, Loic Le Marchand, Line Bjørge, Marina Bermisheva, Agnieszka Podgorska, John Attia, Tracy A. O'Mara, Shashikant Lele, Thomas A. Sellers, Bo Gao, Holly R. Harris, Shan Wang-Gohrke, Lingeng Lu, Louise A. Brinton, Alessandra Macciotta, Digna R. Velez Edwards, Peter A. Fasching, Marc T. Goodman, Linda S. Cook, Constance Turman, Jacek Gronwald, Liv Cecilie Vestrheim Thomsen, Matthias Dürst, Kirsten B. Moysich, Usha Menon, Dong Liang, Arif B. Ekici, Bozena Konopka, Aurelio Barricarte, Thilo Dörk, Stefanie Burghaus, Michael Jones, Loren Lipworth, Zhihua Chen, Xiaoqing Chen, Alison Brand, Iain A. McNeish, Tanja Pejovic, Florian Heitz, Beth Y. Karlan, Anthony J. Swerdlow, Anna H. Wu, Obstetrics and Gynaecology, CCA - Cancer biology and immunology, and Amsterdam Reproduction & Development (AR&D)
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, Quantitative Trait Loci, Genome-wide association study, Biology, Carcinoma, Ovarian Epithelial, Genetic correlation, 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Uterine cancer, Risk Factors, Internal medicine, medicine, Humans, Genetic association, Ovarian Neoplasms, Endometrial cancer, Cancer, medicine.disease, 3. Good health, Endometrial Neoplasms, 030104 developmental biology, 030220 oncology & carcinogenesis, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Human genome, Female, Ovarian cancer, Genome-Wide Association Study
Abstract: Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P < 5 × 10−7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
Published: 2021

40. The Costs and Benefits of Risk Stratification for Colorectal Cancer Screening Based On Phenotypic and Genetic Risk: A Health Economic Analysis

Author: Juliet A. Usher-Smith, Simon J. Griffin, Sophie Whyte, Chloe Thomas, Deborah J. Thompson, Catherine L. Saunders, Olena Mandrik, Thomas, Chloe [0000-0001-8704-3262], Saunders, Catherine L [0000-0002-3127-3218], Thompson, Deborah [0000-0003-1465-5799], Griffin, Simon [0000-0002-2157-4797], Usher-Smith, Juliet A [0000-0002-8501-2531], and Apollo - University of Cambridge Repository
Subjects: Adult, Male, Cancer Research, Colorectal cancer, Cost-Benefit Analysis, Population, MEDLINE, Risk Assessment, State Medicine, Article, Risk Factors, Medicine, Humans, Mass Screening, Genetic Predisposition to Disease, Genetic Testing, Genetic risk, education, Life Style, Early Detection of Cancer, Aged, Aged, 80 and over, education.field_of_study, Framingham Risk Score, Models, Statistical, Cost–benefit analysis, Receiver operating characteristic, business.industry, Incidence (epidemiology), Incidence, Colonoscopy, Middle Aged, medicine.disease, Phenotype, Oncology, England, Occult Blood, Female, business, Colorectal Neoplasms, Demography
Abstract: Population-based screening for colorectal cancer is an effective and cost-effective way of reducing colorectal cancer incidence and mortality. Many genetic and phenotypic risk factors for colorectal cancer have been identified, leading to development of colorectal cancer risk scores with varying discrimination. However, these are not currently used by population screening programs. We performed an economic analysis to assess the cost-effectiveness, clinical outcomes, and resource impact of using risk-stratification based on phenotypic and genetic risk, taking a UK National Health Service perspective. Biennial fecal immunochemical test (FIT), starting at an age determined through risk-assessment at age 40, was compared with FIT screening starting at a fixed age for all individuals. Compared with inviting everyone from age 60, using a risk score with area under the receiver operating characteristic curve of 0.721 to determine FIT screening start age, produces 418 QALYs, costs £247,000, and results in 218 fewer colorectal cancer cases and 156 fewer colorectal cancer deaths per 100,000 people, with similar FIT screening invites. There is 96% probability that risk-stratification is cost-effective, with net monetary benefit (based on £20,000 per QALY threshold) estimated at £8.1 million per 100,000 people. The maximum that could be spent on risk-assessment and still be cost-effective is £114 per person. Lower benefits are produced with lower discrimination risk scores, lower mean screening start age, or higher FIT thresholds. Risk-stratified screening benefits men more than women. Using risk to determine FIT screening start age could improve the clinical outcomes and cost effectiveness of colorectal cancer screening without using significant additional screening resources. Prevention Relevance: Colorectal cancer screening is essential for early detection and prevention of colorectal cancer, but implementation is often limited by resource constraints. This work shows that risk-stratification using genetic and phenotypic risk could improve the effectiveness and cost-effectiveness of screening programs, without using substantially more screening resources than are currently available.
Published: 2020

41. Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan

Author: Alex S. F. Kwong, Peter K. Joshi, Deborah J. Thompson, Doug Easton, Alexander S Busch, Perry Jrb., Ken K. Ong, Felix R. Day, Soares Alg, Benjamin Hollis, and Timmers Prhj
Subjects: Basis (linear algebra), Evolutionary biology, Biology
Published: 2020

42. Association between genetic polymorphisms and endometrial cancer risk:a systematic review

Author: Neil A J Ryan, Anie Naqvi, D. Gareth Evans, Miriam J. Smith, Artitaya Lophatananon, Deborah J. Thompson, Cemsel Bafligil, Emma J Crosbie, Bafligil, Cemsel [0000-0002-2365-1194], Smith, Miriam J [0000-0002-3184-0817], Evans, D Gareth [0000-0002-8482-5784], Crosbie, Emma J [0000-0003-0284-8630], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, genetic epidemiology, MEDLINE, Kruppel-Like Transcription Factors, Single-nucleotide polymorphism, CINAHL, Polymorphism, Single Nucleotide, SOXC Transcription Factors, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, eIF-2 Kinase, risk prediction, 0302 clinical medicine, Aromatase, single nucleotide polymorphism (SNP), systematic review, Risk Factors, Internal medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Prospective Studies, Genetics (clinical), Genetic association, Hepatocyte Nuclear Factor 1-beta, business.industry, Endometrial cancer, Proto-Oncogene Proteins c-mdm2, Publication bias, medicine.disease, HNF1B, Endometrial Neoplasms, 030104 developmental biology, Genetic epidemiology, 030220 oncology & carcinogenesis, endometrial cancer, Female, business, Genome-Wide Association Study
Abstract: Funder: national institute of health research, INTRODUCTION: Endometrial cancer is one of the most commonly diagnosed cancers in women. Although there is a hereditary component to endometrial cancer, most cases are thought to be sporadic and lifestyle related. The aim of this study was to systematically review prospective and retrospective case-control studies, meta-analyses and genome-wide association studies to identify genomic variants that may be associated with endometrial cancer risk. METHODS: We searched MEDLINE, Embase and CINAHL from 2007 to 2019 without restrictions. We followed PRISMA 2009 guidelines. The search yielded 3015 hits in total. Following duplicate exclusion, 2674 abstracts were screened and 453 full-texts evaluated based on our pre-defined screening criteria. 149 articles were eligible for inclusion. RESULTS: We found that single nucleotide polymorphisms (SNPs) in HNF1B, KLF, EIF2AK, CYP19A1, SOX4 and MYC were strongly associated with incident endometrial cancer. Nineteen variants were reported with genome-wide significance and a further five with suggestive significance. No convincing evidence was found for the widely studied MDM2 variant rs2279744. Publication bias and false discovery rates were noted throughout the literature. CONCLUSION: Endometrial cancer risk may be influenced by SNPs in genes involved in cell survival, oestrogen metabolism and transcriptional control. Larger cohorts are needed to identify more variants with genome-wide significance.
Published: 2020

43. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Author: Montserrat Garcia-Closas, Ellen L. Goode, Mark M. Iles, Brian M. Wolpin, Stephen J. Chanock, Susan L. Slager, Li Hsu, Clare Turnbull, Ccfr, Michael Hoffmeister, Peter T. Campbell, Maria Teresa Landi, Paul D.P. Pharoah, Amber N. Hurson, Melissa L. Bondy, Roger L. Milne, Peter A. Kanetsky, Simon A. Gayther, Christopher A. Haiman, Nicola J. Camp, Mark A. Jenkins, Margaret Wrensch, Bcac, Ulrike Peters, Jill S. Barnholtz-Sloan, Richard S. Houlston, PanScan, Haoyu Zhang, Christopher I. Amos, Ben Kinnersley, GenoMEL, Florence Demenais, Rosalind A. Eeles, Katherine A. McGlynn, Practical, John K. Wiencke, Gicc, Katherine L. Nathanson, Stolzenberg-Solomon R, Brenda M. Birmann, Rayjean J. Hung, Donghui Li, David C. Whiteman, Ghislaine Scelo, Sonja I. Berndt, Alison P. Klein, Sarah V. Ward, Per Hall, D. Timothy Bishop, Tracy A. O'Mara, Kirsten B. Moysich, Corect, Laufey T. Amundadottir, Marjanka K. Schmidt, Ian Tomlinson, Ocac, Yan Zhang, Gloria M. Petersen, Ali Amin Al Olama, Puya Gharahkhani, Deborah J. Thompson, Paul Brennan, Douglas F. Easton, Celeste Leigh Pearce, InterLymph, Jacques Simard, Mark H. Greene, Zsofia Kote-Jarai, Nilanjan Chatterjee, Ecac, Marlene Danner Dalgaard, Mark P. Purdue, Beatrice Melin, Graham Casey, Rajesh Kumar, Jenny Chang-Claude, Thomas A. Sellers, Stephen B. Gruber, Beacon, James D. McKay, Tecac, Stephanie L. Schmit, Tom Grotmol, Kyriaki Michailidou, Immaculata De Vivo, Joellen M. Schildkraut, Eric J. Jacobs, Fredrik Wiklund, Amanda B. Spurdle, Nathaniel Rothman, Parichoy Pal Choudhury, Peter Kraft, Panc, Renal Cancer Gwas, Neil E. Caporaso, Joe Dennis, Matthew Law, Fredrick R. Schumacher, Harvey A. Risch, Stuart MacGregor, Andrew Berchuck, Ilcco, Oral Cancer Gwas, Zhang, Yan Dora [0000-0002-5302-3690], Hurson, Amber N. [0000-0001-7831-6660], Easton, Douglas F. [0000-0003-2444-3247], Milne, Roger L. [0000-0001-5764-7268], Simard, Jacques [0000-0001-6906-3390], Michailidou, Kyriaki [0000-0001-7065-1237], Dennis, Joe [0000-0003-4591-1214], Schmidt, Marjanka K. [0000-0002-2228-429X], Gharahkhani, Puya [0000-0002-4203-5952], Whiteman, David [0000-0003-2563-9559], Jenkins, Mark [0000-0002-8964-6160], Peters, Ulrike [0000-0001-5666-9318], Schmit, Stephanie L. [0000-0001-5931-1194], O’Mara, Tracy A. [0000-0002-5436-3232], Spurdle, Amanda B. [0000-0003-1337-7897], Thompson, Deborah J. [0000-0003-1465-5799], Tomlinson, Ian [0000-0003-3037-1470], Landi, Maria Teresa [0000-0003-4507-329X], Law, Matthew H. [0000-0002-4303-8821], Iles, Mark M. [0000-0002-2603-6509], Demenais, Florence [0000-0001-8361-0936], Kumar, Rajiv [0000-0002-6093-0395], MacGregor, Stuart [0000-0001-6731-8142], Bishop, D. Timothy [0000-0002-8752-8785], Houlston, Richard [0000-0002-5268-0242], Barnholtz-Sloan, Jill [0000-0001-6190-9304], Kinnersley, Ben [0000-0003-1783-6296], Amos, Christopher I. [0000-0002-8540-7023], Hung, Rayjean J. [0000-0002-4486-7496], Brennan, Paul [0000-0002-0518-8714], Birmann, Brenda M. [0000-0002-7550-5498], Camp, Nicola J. [0000-0002-4788-1998], Kraft, Peter [0000-0002-4472-8103], Pharoah, Paul D. P. [0000-0001-8494-732X], Gayther, Simon A. [0000-0001-7937-5443], Amundadottir, Laufey T. [0000-0003-1859-8971], Jacobs, Eric J. [0000-0002-8458-7659], Klein, Alison P. [0000-0003-2737-8399], Eeles, Rosalind A. [0000-0002-3698-6241], Schumacher, Fredrick R. [0000-0002-3073-7463], Greene, Mark H. [0000-0003-1852-9239], Kanetsky, Peter A. [0000-0002-5567-9618], Nathanson, Katherine L. [0000-0002-6740-0901], Wiklund, Fredrik [0000-0002-4623-0544], Chanock, Stephen J. [0000-0002-2324-3393], Garcia-Closas, Montserrat [0000-0003-1033-2650], Apollo - University of Cambridge Repository, Hurson, Amber N [0000-0001-7831-6660], Easton, Douglas F [0000-0003-2444-3247], Milne, Roger L [0000-0001-5764-7268], Schmidt, Marjanka K [0000-0002-2228-429X], Schmit, Stephanie L [0000-0001-5931-1194], O'Mara, Tracy A [0000-0002-5436-3232], Spurdle, Amanda B [0000-0003-1337-7897], Thompson, Deborah J [0000-0003-1465-5799], Law, Matthew H [0000-0002-4303-8821], Iles, Mark M [0000-0002-2603-6509], Bishop, D Timothy [0000-0002-8752-8785], Amos, Christopher I [0000-0002-8540-7023], Hung, Rayjean J [0000-0002-4486-7496], Birmann, Brenda M [0000-0002-7550-5498], Camp, Nicola J [0000-0002-4788-1998], Pharoah, Paul DP [0000-0001-8494-732X], Gayther, Simon A [0000-0001-7937-5443], Amundadottir, Laufey T [0000-0003-1859-8971], Jacobs, Eric J [0000-0002-8458-7659], Klein, Alison P [0000-0003-2737-8399], Eeles, Rosalind A [0000-0002-3698-6241], Schumacher, Fredrick R [0000-0002-3073-7463], Greene, Mark H [0000-0003-1852-9239], Kanetsky, Peter A [0000-0002-5567-9618], Nathanson, Katherine L [0000-0002-6740-0901], and Chanock, Stephen J [0000-0002-2324-3393]
Subjects: Male, 0301 basic medicine, Oncology, Multifactorial Inheritance, 45/43, General Physics and Astronomy, Diseases, Genome-wide association study, 0302 clinical medicine, Risk Factors, Neoplasms, 631/208/68, lcsh:Science, Cancer genetics, Multidisciplinary, 692/699, Incidence, article, 030220 oncology & carcinogenesis, Medical genetics, Female, Medical Genetics, medicine.medical_specialty, Science, Biology, Polymorphism, Single Nucleotide, Risk Assessment, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Genetic predisposition, Animals, Humans, Genetic Predisposition to Disease, Lung cancer, Genetic association, Medicinsk genetik, Cancer och onkologi, Models, Genetic, 45, Cancer, General Chemistry, Heritability, medicine.disease, 030104 developmental biology, Sample size determination, Relative risk, Cancer and Oncology, lcsh:Q, Ovarian cancer, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence., In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.
Published: 2020

44. Combining genome-wide studies of breast, prostate, ovarian and endometrial cancers maps cross-cancer susceptibility loci and identifies new genetic associations

Author: Rosalind A. Eeles, Anne van Altena, Rüdiger Klapdor, Rayjean J. Hung, Graham G. Giles, Ingo B. Runnebaum, Stacey J. Winham, Alicia Beeghly-Fadiel, Michelle A.T. Hildebrandt, Ruea-Yea Huang, Amanda B. Spurdle, Ahmad Alsulimani, Robert Winqvist, Robert J. Hamilton, Clare Turnbull, James M. Flanagan, Jan Gawełko, Kenneth Muir, Peter Kraft, Joseph Vijai, Anna Jakubowska, Paul D.P. Pharoah, Stephen J. Chanock, Ailith Ewing, Mary B. Daly, Artitaya Lophatananon, Arvids Irmejs, Hiltrud Brauch, Paolo Radice, Camilla Krakstad, Liher Imaz, Lambertus A. Kiemeney, Clara Bodelon, Nadeem Siddiqui, Alvaro N.A. Monteiro, Bozena Konopka, Taymaa May, Herbert Yu, Stefanie Burghaus, Michael E. Carney, Siddhartha Kar, Beata Spiewankiewicz, Fernando Moreno Antón, Andreas du Bois, Sune F. Nielsen, Ian Tomlinson, Elza Khusnutdinova, Paolo Peterlongo, Zhihua Chen, Deborah J. Thompson, Agnieszka Podgorski, Päivi Kannisto, Andrew Berchuck, Jenny Chang-Claude, Susan J. Ramus, Florian Heitz, Nawaid Usmani, Tracy A. O'Mara, Joellen M. Schildkraut, Jennifer Permuth, Beth Y. Karlan, Ignace Vergote, Douglas F. Easton, Sara Lindstroem, Agnieszka Mieszkowska, Kirsten B. Moysich, Ana Vega-Gliemmo, Simon A. Gayther, Arif B. Ekici, Lukasz Szafron, Kunle Odunsi, Marjanka K. Schmidt, Harvey A. Risch, Linda J. Titus, Weiva Sieh, Robert A. Vierkant, Davor Lessel, Line Bjørge, Allan Jensen, Wei Zheng, Holly R. Harris, Petra Kleiblova, Peter A. Fasching, Jonathan Tyrer, Iwona K. Rzepecka, Georgia Chenevix-Trench, Tjoung-Won Park-Simon, Susanne K. Kjaer, Esther M. John, Daniele Campa, Veronica Wendy Setiawan, Martin Koebel, Cheryl L. Thompson, Håkan Olsson, Dylan M. Glubb, Peter Hillemanns, and Kate Lawrenson
Subjects: Oncology, medicine.medical_specialty, Endometrial cancer, Cancer susceptibility, Susceptibility gene, Effective sample size, Biology, medicine.disease, Genome, medicine.anatomical_structure, Prostate, Internal medicine, medicine, Genetic association
Abstract: We report a meta-analysis of breast, prostate, ovarian, and endometrial cancer genome-wide association data (effective sample size: 237,483 cases/317,006 controls). This identified 465 independent lead variants (P−8) across 192 genomic regions. Four lead variants were >1Mb from previously identified risk loci for the four cancers and an additional 23 lead variant-cancer associations were novel for one of the cancers. Bayesian models supported pleiotropic effects involving at least two cancers at 222/465 lead variants in 118/192 regions. Gene-level association analysis identified 13 shared susceptibility genes (P−6) in 13 regions not previously implicated in any of the four cancers and not uncovered by our variant-level meta-analysis. Several lead variants had opposite effects across cancers, including a cluster of such variants in the TP53 pathway. Fifty-four lead variants were associated with blood cell traits and suggested genetic overlaps with clonal hematopoiesis. Our study highlights the remarkable pervasiveness of pleiotropy across hormone-related cancers, further illuminating their shared genetic and mechanistic origins at variant- and gene-level resolution.
Published: 2020

45. Cross-cancer genome-wide association study of endometrial cancer and epithelial ovarian cancer identifies genetic risk regions associated with risk of both cancers

Author: Clara Bodelon, Anna H. Wu, V. Wendy Setiawan, Jenny Lester, Adriaan Vanderstichele, Daniela Annibali, Michael E. Carney, Jennifer A. Doherty, Shashikant Lele, Jacek Gronwald, Matthias W. Beckmann, George Fountzilas, Christine M. Friedenreich, Heli Nevanlinna, Immaculata De Vivo, Jolanta Lissowska, Soo Hwang Teo, Ahmad Alsulimani, Daniel D. Buchanan, Rosalind Glasspool, Domenico Palli, Madhuri Koti, Katja K.H. Aben, Tanja Pejovic, Linda S. Cook, Line Bjørge, Mia M. Gaudet, Anna Jakubowska, Tomasz Huzarski, Florian Heitz, Beth Y. Karlan, Andreas du Bois, Linda J. Titus, Joseph L. Kelley, Andrew Berchuck, Aleksandra Gentry-Maharaj, Florentia Fostira, Weiva Sieh, Anthony J. Swerdlow, Celeste Leigh Pearce, Constance Turman, Zhaoming Wang, Ignace Vergote, Dylan M. Glubb, Peter Hillemanns, Chu Chen, Tjoung-Won Park-Simon, Andrew J. Li, Susanne K. Kjaer, Jan Gawełko, Stephen J. Chanock, Tracy A. O'Mara, Elizabeth G. Holliday, Jessica N. McAlpine, Ailith Ewing, Amalia Mattiello, Pamela J. Thompson, Xifeng Wu, Alicia A. Tone, Ana Osorio, Fiona Bruinsma, Digna R. Velez Edwards, Janine Senz, Francesmary Modugno, Michael Jones, Sandra Orsulic, Xiaoqing Chen, Todd L. Edwards, Aurelio Barricarte, Hui Cai, Loren Lipworth, David G. Huntsman, Zhihua Chen, Alison M. Dunning, Julie M. Cunningham, Rosario Tumino, Melissa C. Larson, Ralf Bützow, Alison Brand, Allan Jensen, Marina Bermisheva, Reidun K. Kopperud, Beata Spiewankiewicz, Timothy R. Rebbeck, Bozena Konopka, Matthias Dürst, Thomas A. Sellers, Penelope M. Webb, Claus Høgdall, Anthony N. Karnezis, Håkan Olsson, Liv Cecilie Vestrheim Thomsen, Rodney J. Scott, Iain A. McNeish, Arif B. Ekici, Valerie McGuire, Lukasz Szafron, Harvey A. Risch, Bo Gao, Louise A. Brinton, Alessandra Macciotta, Anna deFazio, Rüdiger Klapdor, Graham G. Giles, Usha Menon, Marc T. Goodman, Robert P. Edwards, Robert A. Vierkant, Dong Liang, Shan Wang-Gohrke, Lingeng Lu, Kirsten B. Moysich, Holly R. Harris, Deborah J. Thompson, Jennifer B. Permuth, Alexander Hein, Thilo Dörk, Elza Khusnutdinova, Stefanie Burghaus, Irene Konstantopoulou, Stacey J. Winham, Susan J. Ramus, Agnieszka Podgorska, Rebecca Sutphen, Michelle A.T. Hildebrandt, Jolanta Kupryjanczyk, Ingo B. Runnebaum, James D. Brenton, Karen H. Lu, Katharina Bischof, Nadeem Siddiqui, Drakoulis Yannoukakos, Estrid Høgdall, John Attia, Clemens Liebrich, Loic Le Marchand, Emily White, Amanda B. Spurdle, Peter Kraft, Alice S. Whittemore, Kunle Odunsi, Sarah E. Ferguson, Taymaa May, Marjorie J. Riggan, Philipp Harter, Jeffrey Killeen, James M. Flanagan, Frédéric Amant, Marcus Q. Bernardini, Joseph H. Rothstein, Martin Köbel, Peter A. Fasching, and Diether Lambrechts
Subjects: Oncology, 0303 health sciences, medicine.medical_specialty, business.industry, Endometrial cancer, Genome-wide association study, medicine.disease, Genetic correlation, 3. Good health, 03 medical and health sciences, Serous fluid, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, Epidemiology, medicine, Epithelial ovarian cancer, business, Clear cell, 030304 developmental biology, Genetic association
Abstract: Accumulating evidence suggests a relationship between endometrial cancer and epithelial ovarian cancer. For example, endometrial cancer and epithelial ovarian cancer share epidemiological risk factors and molecular features observed across histotypes are held in common (e.g. serous, endometrioid and clear cell). Independent genome-wide association studies (GWAS) for endometrial cancer and epithelial ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. Using GWAS summary statistics, we explored the shared genetic etiology between endometrial cancer and epithelial ovarian cancer. Genetic correlation analysis using LD Score regression revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses by stratified by subtype. We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified at a sub-genome wide threshold (P < 5 × 10−7). Integration with promoter-associated HiChIP chromatin loops from immortalized endometrium and epithelial ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation.
Published: 2020
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46. External Validation of Risk Prediction Models Incorporating Common Genetic Variants for Incident Colorectal Cancer Using UK Biobank

Author: Jon Emery, Joe Dennis, Britt Kilian, Antonis C. Antoniou, Simon J. Griffin, Xin Yang, Luke McGeoch, Deborah J. Thompson, Juliet A. Usher-Smith, Catherine L. Saunders, Fiona M Walter, Kilian, Britt [0000-0003-1493-2768], Thompson, Deborah J [0000-0003-1465-5799], McGeoch, Luke J [0000-0002-1109-0238], Griffin, Simon J [0000-0002-2157-4797], Antoniou, Antonis C [0000-0001-9223-3116], Emery, Jon D [0000-0002-5274-6336], Walter, Fiona M [0000-0002-7191-6476], Dennis, Joe [0000-0003-4591-1214], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, Adult, Male, Risk, Cancer Research, medicine.medical_specialty, Colorectal cancer, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Sex Factors, Internal medicine, Ethnicity, Medicine, Humans, Registries, Aged, Biological Specimen Banks, Models, Genetic, business.industry, Incidence (epidemiology), Incidence, Age Factors, Cancer, Middle Aged, medicine.disease, Biobank, Confidence interval, United Kingdom, 030104 developmental biology, 030220 oncology & carcinogenesis, Relative risk, Area Under Curve, Cohort, Female, business, Colorectal Neoplasms
Abstract: The aim of this study was to compare and externally validate risk scores developed to predict incident colorectal cancer that include common genetic variants (SNPs), with or without established lifestyle/environmental (questionnaire-based/classical/phenotypic) risk factors. We externally validated 23 risk models from a previous systematic review in 443,888 participants ages 37 to 73 from the UK Biobank cohort who had 6-year prospective follow-up, no prior history of colorectal cancer, and data for incidence of colorectal cancer through linkage to national cancer registries. There were 2,679 (0.6%) cases of incident colorectal cancer. We assessed model discrimination using the area under the operating characteristic curve (AUC) and relative risk calibration. The AUC of models including only SNPs increased with the number of included SNPs and was similar in men and women: the model by Huyghe with 120 SNPs had the highest AUC of 0.62 [95% confidence interval (CI), 0.59–0.64] in women and 0.64 (95% CI, 0.61–0.66) in men. Adding phenotypic risk factors without age improved discrimination in men but not in women. Adding phenotypic risk factors and age increased discrimination in all cases (P < 0.05), with the best performing models including SNPs, phenotypic risk factors, and age having AUCs between 0.64 and 0.67 in women and 0.67 and 0.71 in men. Relative risk calibration varied substantially across the models. Among middle-aged people in the UK, existing polygenic risk scores discriminate moderately well between those who do and do not develop colorectal cancer over 6 years. Consideration should be given to exploring the feasibility of incorporating genetic and lifestyle/environmental information in any future stratified colorectal cancer screening program.
Published: 2020
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47. Psychological impact and acceptability of magnetic resonance imaging and X-ray mammography: the MARIBS Study

Author: J Hutton, Gek Kwan-Lim, DM Sharp, LJ Pointon, Rosalind A. Eeles, Leslie G. Walker, Deborah J. Thompson, D. G. Evans, Martin O. Leach, Fiona J. Gilbert, Gilbert, Fiona [0000-0002-0124-9962], Thompson, Deborah [0000-0003-1465-5799], and Apollo - University of Cambridge Repository
Subjects: Adult, Cancer Research, Cost-Benefit Analysis, Radiography, Population, Breast Neoplasms, psychology, breast cancer, Breast cancer, MARIBS, Surveys and Questionnaires, Outcome Assessment, Health Care, medicine, Humans, Mammography, Family history, education, education.field_of_study, medicine.diagnostic_test, business.industry, X-Rays, Carcinoma, Magnetic resonance imaging, Middle Aged, Patient Acceptance of Health Care, anxiety, medicine.disease, Magnetic Resonance Imaging, Adult Breast Neoplasms/psychology/*radiography Carcinoma/psychology/*radiography Cost-Benefit Analysis Disease Susceptibility Female Follow-Up Studies Humans Magnetic Resonance Imaging/economics/*methods/psychology Mammography/economics/*methods/*psychology Middle Aged Outcome Assessment (Health Care) *Patient Acceptance of Health Care/psychology/statistics & numerical data Questionnaires X-Rays, Distress, Oncology, Clinical Study, Female, Disease Susceptibility, Breast disease, business, Nuclear medicine, Follow-Up Studies, MRI
Abstract: BACKGROUND: As part of the Magnetic Resonance Imaging for Breast Screening (MARIBS), Study women with a family history of breast cancer were assessed psychologically to determine the relative psychological impact and acceptability of annual screening using magnetic resonance imaging (MRI) and conventional X-ray mammography (XRM). METHODS: Women were assessed psychologically at baseline (4 weeks before MRI and XRM), immediately before, and immediately after, both MRI and XRM, and at follow-up (6 weeks after the scans). RESULTS: Overall, both procedures were found to be acceptable with high levels of satisfaction (MRI, 96.3% and XRM, 97.7%; NS) and low levels of psychological morbidity throughout, particularly at 6-week follow-up. Low levels of self-reported distress were reported for both procedures (MRI, 13.5% and XRM, 7.8%), although MRI was more distressing (P=0.005). Similarly, higher anticipatory anxiety was reported before MRI than before XRM (P=0.003). Relative to XRM, MRI-related distress was more likely to persist at 6 weeks after the scans in the form of intrusive MRI-related thoughts (P=0.006) and total MRI-related distress (P=0.014). More women stated that they intended to return for XRM (96.3%) than for MRI (88%; P, The national study is supported by a grant from the UK Medical Research Council (G960413)
Published: 2020
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48. Impact of a Central-Line Insertion Site Assessment (CLISA) score on localized insertion site infection to prevent central-line-associated bloodstream infection (CLABSI)

Author: Jennifer Yim, Mohamad N. Alsharif, Tom Tjoa, Scott E. Rudkin, Allen Kong, Maurice Espinoza, Usme Khusbu, Linda Dickey, William C. Wilson, Justin Chang, Kathleen A. Quan, Syma Rashid, Bardia Bahadori, Deborah J. Thompson, Alpesh Amin, Shruti K. Gohil, Suzie S. Hong, Susan S. Huang, and Chris Paiji
Subjects: Microbiology (medical), Adult, Male, medicine.medical_specialty, Epidemiology, Oncology Service, Insertion site, Bacteremia, 030501 epidemiology, Medical and Health Sciences, California, law.invention, 03 medical and health sciences, Hospital, 0302 clinical medicine, law, Clinical Research, Risk Factors, Bloodstream infection, Internal medicine, Oncology Service, Hospital, Medicine, Humans, Central Venous Catheters, 030212 general & internal medicine, Retrospective Studies, Aged, Central line, Cross Infection, Infection Control, Academic Medical Centers, business.industry, Incidence (epidemiology), Prevention, Incidence, Retrospective cohort study, Odds ratio, Middle Aged, Intensive care unit, Confidence interval, Intensive Care Units, Infectious Diseases, Catheter-Related Infections, Regression Analysis, Female, 0305 other medical science, business
Abstract: Objective:To assess the impact of a newly developed Central-Line Insertion Site Assessment (CLISA) score on the incidence of local inflammation or infection for CLABSI prevention.Design:A pre- and postintervention, quasi-experimental quality improvement study.Setting and participants:Adult inpatients with central venous catheters (CVCs) hospitalized in an intensive care unit or oncology ward at a large academic medical center.Methods:We evaluated CLISA score impact on insertion site inflammation and infection (CLISA score of 2 or 3) incidence in the baseline period (June 2014–January 2015) and the intervention period (April 2015–October 2017) using interrupted times series and generalized linear mixed-effects multivariable analyses. These were run separately for days-to-line removal from identification of a CLISA score of 2 or 3. CLISA score interrater reliability and photo quiz results were evaluated.Results:Among 6,957 CVCs assessed 40,846 times, percentage of lines with CLISA score of 2 or 3 in the baseline and intervention periods decreased by 78.2% (from 22.0% to 4.7%), with a significant immediate decrease in the time-series analysis (P < .001). According to the multivariable regression, the intervention was associated with lower percentage of lines with a CLISA score of 2 or 3, after adjusting for age, gender, CVC body location, and hospital unit (odds ratio, 0.15; 95% confidence interval, 0.06–0.34; P < .001). According to the multivariate regression, days to removal of lines with CLISA score of 2 or 3 was 3.19 days faster after the intervention (P < .001). Also, line dwell time decreased 37.1% from a mean of 14 days (standard deviation [SD], 10.6) to 8.8 days (SD, 9.0) (P < .001). Device utilization ratios decreased 9% from 0.64 (SD, 0.08) to 0.58 (SD, 0.06) (P = .039).Conclusions:The CLISA score creates a common language for assessing line infection risk and successfully promotes high compliance with best practices in timely line removal.
Published: 2020

49. Physical activity and risk of breast and endometrial cancers: a Mendelian randomization study

Author: Sebastian E. Baumeister, Hansjörg Baurecht, Alexander Teumer, Michael F. Leitzmann, Tracy A. O'Mara, and Deborah J. Thompson
Subjects: Oncology, 0303 health sciences, medicine.medical_specialty, business.industry, Endometrial cancer, Confounding, Estrogen receptor, Odds ratio, medicine.disease, Lower risk, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, 030220 oncology & carcinogenesis, Internal medicine, Mendelian randomization, Genetic predisposition, Medicine, business, 030304 developmental biology
Abstract: ImportanceThe causality of the association between physical activity and risk of breast and endometrial cancers is uncertain because available evidence is based exclusively on observational studies, which are potentially susceptible to confounding and reverse causation.ObjectiveTo investigate whether increased physical activity is causally associated with decreased risk of breast and endometrial cancers, using a two-sample Mendelian randomization study design.Design, Setting, and ParticipantsGenome-wide association studies of physical activity, breast cancer, and endometrial cancer, published up to April 31, 2019, were identified using PubMed and the GWAS catalog. Twelve single nucleotide polymorphisms (SNP) known at P < 5 × 10−8 to be associated with accelerometer-assessed or self-reported physical activity served as instrumental variables. Genetic summary data from four large consortia provided SNP-outcome associations [Breast Cancer Association Consortium; Discovery, Biology and Risk of Inherited Variants in Breast Cancer Consortium; Endometrial Cancer Association Consortium].Main Outcomes and MeasuresThe primary outcomes were risk of breast cancer and risk of endometrial cancer. Secondary outcomes were estrogen receptor positive (ER+) and ER-breast cancers. Odds ratios (ORs) and 95% confidence intervals (CIs) per mean acceleration in milli-gravities of accelerometer-assessed physical activity and per one standard deviation (1-SD) increase in metabolic-equivalent (MET)-minutes/week of self-reported moderate-to-vigorous physical activity were computed using the inverse variance weighted method. A series of sensitivity analyses addressed the potential impact of heterogeneity, pleiotropy, and outliers.ResultsSummary data were available for 122,977 breast cancers and 12,270 endometrial cancers. Genetic predisposition to increased accelerometer-assessed physical activity was associated with lower risk of breast and endometrial cancers. The associations (ORs [95% CI] per 1-SD increase in mean acceleration) were 0.88 (0.85-0.91) for breast cancer and 0.90 (0.83-0.97) for endometrial cancer. In addition, genetic predisposition to increased accelerometer-assessed physical activity was associated with lower risk of ER+ breast cancer. We found no evidence for an association between genetic predisposition to self-reported physical activity and risk of total breast cancer, breast cancer subtypes, or endometrial cancer.Conclusion and RelevanceThis first Mendelian randomization study shows that objectively-assessed physical activity plays a causal role in protecting against breast and endometrial cancers.
Published: 2019
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50. Risk prediction models for colorectal cancer incorporating common genetic variants: a systematic review

Author: Luke McGeoch, Juliet A. Usher-Smith, Simon J. Griffin, Jon Emery, Antonis C. Antoniou, Catherine L. Saunders, Fiona M Walter, Deborah J. Thompson, Griffin, Simon J [0000-0002-2157-4797], Emery, Jon D [0000-0002-5274-6336], Walter, Fiona M [0000-0002-7191-6476], Thompson, Deborah J [0000-0003-1465-5799], Antoniou, Antonis C [0000-0001-9223-3116], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, Population, MEDLINE, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, Risk Assessment, Article, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Risk Factors, Internal medicine, medicine, Biomarkers, Tumor, SNP, Humans, education, Early Detection of Cancer, Genetic association, education.field_of_study, Models, Statistical, business.industry, Cancer, medicine.disease, Prognosis, 030104 developmental biology, 030220 oncology & carcinogenesis, Risk assessment, business, Colorectal Neoplasms, Genome-Wide Association Study
Abstract: Colorectal cancer screening reduces colorectal cancer incidence and mortality. Risk models based on phenotypic variables have relatively good discrimination in external validation and may improve efficiency of screening. Models incorporating genetic variables may perform better. In this review, we updated our previous review by searching Medline and EMBASE from the end date of that review (January 2014) to February 2019 to identify models incorporating at least one SNP and applicable to asymptomatic individuals in the general population. We identified 23 new models, giving a total of 29. Of those in which the SNP selection was on the basis of published genome-wide association studies, in external or split-sample validation the AUROC was 0.56 to 0.57 for models that included SNPs alone, 0.61 to 0.63 for SNPs in combination with other risk factors, and 0.56 to 0.70 when age was included. Calibration was only reported for four. The addition of SNPs to other risk factors increases discrimination by 0.01 to 0.06. Public health modeling studies suggest that, if determined by risk models, the range of starting ages for screening would be several years greater than using family history alone. Further validation and calibration studies are needed alongside modeling studies to assess the population-level impact of introducing genetic risk–based screening programs.
Published: 2019

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