Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-staged approach to conduct genome-wide association studies for lung, ovary, breast, prostate and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression.
Cancer research. 2016 Apr 20 [Epub ahead of print]
Gordon Fehringer, Peter Kraft, Paul D P Pharoah, Rosalind A Eeles, Nilanjan Chatterjee, Fredrick R Schumacher, Joellen M Schildkraut, Sara Lindstrom, Paul Brennan, Heike Bickeböller, Richard S Houlston, Maria Teresa Landi, Neil E Caporaso, Angela Risch, Ali Amin Al Olama, Sonja I Berndt, Edward Giovannucci, Henrik Gronberg, Zsofia Kote-Jarai, Jing Ma, Kenneth Muir, Meir J Stampfer, Victoria L Stevens, Fredrik Wiklund, Walter C Willett, Ellen L Goode, Jennifer B Permuth, Harvey A Risch, Brett M Reid, Stéphane Bezieau, Hermann Brenner, Andrew T Chan, Jenny Chang-Claude, Thomas J Hudson, Jonathan Kocarnik, Polly A Newcomb, Robert E Schoen, Martha L Slattery, Emily White, Muriel A Adank, Habibul Ahsan, Kristiina Aittomaki, Laura Baglietto, Carl Blomquist, Federico Canzian, Kamila Czene, Isabel Dos Santos Silva, A Heather Eliassen, Jonine D Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Montserrat Garcia-Closas, Mia M Gaudet, Nichola Johnson, Per Hall, Aditi Hazra, Rebecca Hein, Albert Hofman, John L Hopper, Astrid Irwanto, Mattias Johansson, Rudolf Kaaks, Muhammad G Kibriya, Peter Lichtner, Jian-Jun Liu, Eiliv Lund, Enes Makalic, Alfons Meindl, Bertram Müller-Myhsok, Taru A Muranen, Heli Nevanlinna, Petra H Peeters, Julian Peto, Ross L Prentice, Nazneen Rahman, Maria-Jose Sanchez, Daniel F Schmidt, Rita K Schmutzler, Melissa C Southey, Rulla M Tamimi, Ruth C Travis, Clare Turnbull, Andre G Uitterlinden, Zhaoming Wang, Alice S Whittemore, Xiaohong R Yang, Wei Zheng, Thorunn Rafnar, Julius Gudmundsson, Simon N Stacey, Kari Stefansson, Patrick Sulem, Y Ann Chen, Jonathan P Tyrer, David C Christiani, Yongyue Wei, Hongbing Shen, Zhibin Hu, Xiao-Ou Shu, Kouya Shiraishi, Atsushi Takahashi, Yohan Bossé, Ma'en Obeidat, David Nickle, Wim Timens, Matthew L Freedman, Qiyuan Li, Daniela Seminara, Stephen J Chanock, Jian Gong, Ulrike Peters, Stephen B Gruber, Christopher I Amos, Thomas A Sellers, Douglas F Easton, David J Hunter, Christopher A Haiman, Brian E Henderson, Rayjean J Hung
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital., Department of Epidemiology, Harvard TH Chan School of Public Health., Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge., The Institute of Cancer Research., Division of Cancer Epidemiology and Genetics, National Cancer Institute., Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California., Department of Public Health Sciences,, University of Virginia., Department of Epidemiology, Harvard School of Public Health., Section of Genetics, International Agency for Research on Cancer., Department of Genetic Epidemiology, Georg-August University of Göttingen., Institute of Cancer Research., Division of Cancer Epidemiology and Genetics, National Cancer Institute., Division of Cancer Epidemiology and Genetics, National Cancer Institute., German Cancer Research Center (DKFZ) Heidelberg, Germany., Public Health and Primary Care, University of Cambridge., Cancer Epidemiology and Genetics, National Cancer Institute., Epidemiology, Harvard T.H. Chan School of Public Health., Department of Medical Epidemiology and Biostatistics, Karolinska Institute., The Institute of Cancer Research., Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School., The University of Manchester., Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School., Epidemiology Research, American Cancer Society., Department of Medical Epidemiology and Biostatistics, Karolinska Institute., Department of Nutrition, Harvard T.H. Chan School of Public Health., Department of Health Sciences Research, Mayo Clinic., Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute., Chronic Disease Epidemiology, Yale School of Public Health., Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute., Université de Nantes., Division of Clinical Epidemiology and Aging Research, German Cancer Research Center., Department of Gastroenterology, Massachusetts General Hospital, Harvard Medical School., Division of Cancer Epidemiology, German Center for Cancer Research (DKFZ)., Ontario Institute for Cancer Research., Fred Hutchinson Cancer Research Center., Fred Hutchinson Cancer Research Center., Department of Medicine and Epidemiology, University of Pittsburgh Medical Center., Department of Internal Medicine, University of Utah Health Sciences Center., Fred Hutchinson Cancer Research Center., VU University Medical Center., Department of Public Health Sciences, University of Chicago., Department of Clinical Genetics, Helsinki University Central Hospital., Centre for Epidemiology and Biostatistics, The University of Melbourne., University of Helsinki and Helsinki University Central Hospital., Genomic Epidemiology Group, German Cancer Research Center (DKFZ)., Department of Medical Epidemiology and Biostatistics, Karolinska Institutet., Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine., Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School., Division of Cancer Epidemiology and Genetics, National Cancer Institute., Cancer Epidemiology & Clinical Cancer Registry, University Medical Center Hamburg-Eppendorf., Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research., Division of Cancer Epidemiology and Genetics, National Cancer Institute., Epidemiology Research Program, American Cancer Society., Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research., Department of Medical Epidemiology and Biostatistics, Karolinska Institutet., Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School., Cancer Epidemiology, German Cancer Research Center (DKFZ)., Epidemiology, Erasmus Medical Center., Melbourne School of Population Health, The University of Melbourne., Human Genetics, Genome Institute of Singapore., Genetic Epidemiology Group, International Agency for Research on Cancer., Division of Cancer Epidemiology, German Cancer Research Center (DKFZ)., Department of Public Health Sciences, The University of Chicago., Genome Analysis Center, German Research Center for Environmental Health., Human Genetics, Genome Institute of Singapore., Institute of Community Medicine, Faculty of Health Sciences, UiT The Artic University of Norway., Melbourne School of Population Health, The University of Melbourne., Department of Gynaecology and Obstetrics, Technical University Munich., Translational Research in Psychiatry, Max Planck Institute of Psychiatry., Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital., Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital., Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht., Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine., Public Health Science Division, Fred Hutchinson Cancer Research Center., Division of Genetics and Epidemiology, Institute of Cancer Research., CIBER de Epidemiología y Salud Pública (CIBERESP)., Melbourne School of Population Health, The University of Melbourne., Center for Hereditary Breast and Ovarian Cancer, University of Cologne., Genetic Epidemiology Laboratory, The University of Melbourne., Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School., Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford., Section of Cancer Genetics, The Institite of Cancer Research., Department of Epidemiology, Erasmus Medical Center., Division of Cancer Epidemiology and Genetics, National Cancer Institute., Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine., Division of Cancer Epidemiology and Genetics, National Cancer Institute., Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine., Cancer, deCODE genetics., Cancer, deCODE genetics., Cancer, deCODE Genetics., Cancer, deCODE genetics., Cancer, deCODE genetics., Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute., Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge., Department of Epidemiology, Harvard TH Chan School of Public Health., Department of Epidemiology, Harvard TH Chan School of Public Health., Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University., State Key Laboratory of Reproductive Medicine, Nanjing Medical University., Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine., Division of Genome Biology, National Cancer Center Research Institute., Lab for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN., Molecular Medicine, Laval University, Institut universitaire de cardiologie et de pneumologie de Québec., Centre for Heart Lung, Innovation, University of British Columbia Centre for Heart Lung, Innovation, St. Paul's Hospital., Merck Research Laboratories, Merck & Co., Department of Pathology, University of Groningen and University Medical Center Groningen., Dana-Farber Cancer Institute., Medical College, Xiamen University., Division of Cancer Epidemiology and Genetics, National Cancer Institute., Division of Cancer Epidemiology and Genetics, National Cancer Institute; National Institute of Health., Public Health Science, Fred Hutchinson Cancer Research Center., Public Health Science, Fred Hutchinson Cancer Research Center., Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California., Biomedical Data Science, Dartmouth Geisel School of Medicine., Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute., Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge., Department of Epidemiology, Harvard TH Chan School of Public Health., Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California., Preventive Medicine, Keck School of Medicine, University of Southern California., Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital .