Cross-cancer genome-wide analysis of lung, ovary, breast, prostate and colorectal cancer reveals novel pleiotropic associations.

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. 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