Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations
Authors: Fehringer Gordon , Kraft Peter , Pharoah Paul D. , Eeles Rosalind A. , Chatterjee Nilanjan , Schumacher Fredrick R. , Schildkraut Joellen M. , Lindström Sara , Brennan Paul , Bickeböller Heike , Houlston Richard S. , Landi Maria Teresa , Caporaso Neil , Risch Angela , Amin Al Olama Ali , Berndt Sonja I. , Giovannucci Edward L. , Grönberg Henrik , Kote-Jarai Zsofia , Ma Jing , Muir Kenneth , Stampfer Meir J. , Stevens Victoria L. , Wiklund Fredrik , Willett Walter C. , Goode Ellen L. , Permuth Jennifer B. , Risch Harvey A. , Reid Brett M. , Bezieau Stephane , Brenner Hermann , Chan Andrew T. , Chang-Claude Jenny , Hudson Thomas J. , Kocarnik Jonathan K. , Newcomb Polly A. , Schoen Robert E. , Slattery Martha L. , White Emily , Adank Muriel A. , Ahsan Habibul , Aittomäki Kristiina , Baglietto Laura , Blomquist Carl , Canzian Federico , Czene Kamila , dos-Santos-Silva Isabel , Eliassen A. Heather , Figueroa Jonine D. , Flesch-Janys Dieter , Fletcher Olivia , Garcia-Closas Montserrat , Gaudet Mia M. , Johnson Nichola , Hall Per , Hazra Aditi , Hein Rebecca , Hofman Albert , Hopper John L. , Irwanto Astrid , Johansson Mattias , Kaaks Rudolf , Kibriya Muhammad G. , Lichtner Peter , Liu Jianjun , Lund Eiliv , Makalic Enes , Meindl Alfons , Müller-Myhsok Bertram , Muranen Taru A. , Nevanlinna Heli , Peeters Petra H. , Peto Julian , Prentice Ross L. , Rahman Nazneen , Sanchez Maria Jose , Schmidt Daniel F. , Schmutzler Rita K. , Southey Melissa C. , Tamimi Rulla , Travis Ruth C. , Turnbull Clare , Uitterlinden Andre G. , Wang Zhaoming , Whittemore Alice S. , Yang Xiaohong R. , Zheng Wei , Buchanan Daniel D. , Casey Graham , Conti David V. , Edlund Christopher K. , Gallinger Steven , Haile Robert W. , Jenkins Mark , Le Marchand Loïc , Li Li , Lindor Noralene M. , Schmit Stephanie L. , Thibodeau Stephen N. , Woods Michael O. , Rafnar Thorunn , Gudmundsson Julius , Stacey Simon N. , Stefansson Kari , Sulem Patrick , Chen Y. Ann , Tyrer Jonathan P. , Christiani David C. , Wei Yongyue , Shen Hongbing , Hu Zhibin , Shu Xiao-Ou , Shiraishi Kouya , Takahashi Atsushi , Bossé Yohan , Obeidat Ma'en , Nickle David , Timens Wim , Freedman Matthew L. , Li Qiyuan , Seminara Daniela , Chanock Stephen J. , Gong Jian , Peters Ulrike , Gruber Stephen B. , Amos Christopher I. , Sellers Thomas A. , Easton Douglas F. , Hunter David J. , Haiman Christopher A. , Henderson Brian E. , Hung Rayjean J. 
Published: April 2016

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage 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 Res; 76(17); 5103–14. ©2016 AACR.