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

Authors: Siddhartha Kar, Jonathan Beesley, Ali Amin Al Olama, Kyriaki Michailidou, Jonathan P. Tyrer, Zsofia Kote‐Jarai, Kate Lawrenson, Sara Lindström, Susan J. Ramus, Deborah J. Thompson, ABCTB Investigators, Adam S. Kibel, Agnieszka Dansonka‐Mieszkowska, Agnieszka Michael, Aida Karina Dieffenbach, Aleksandra Gentry‐Maharaj, Alice S. Whittemore, Alicja Wolk, Álvaro N.A. Monteiro, Ana Peixoto, Andrzej Kierzek, Angela Cox, Anja Rudolph, Anna González‐Neira, Anna H. Wu, Annika Lindblom, Anthony J. Swerdlow, AOCS Study Group & Australian Cancer Study (Ovarian Cancer), APCB BioResource, Argyrios Ziogas, Arif B. Ekici, Barbara Burwinkel, Beth Y. Karlan, Børge G. Nordestgaard, Carl Blomqvist, Catherine Phelan, Catriona McLean, Celeste Leigh Pearce, Celine M. Vachon, Cezary Cybulski, Chavdar Slavov, Christa Stegmaier, Christiane Maier, Christine B. Ambrosone, Claus Høgdall, Craig C. Teerlink, Daehee Kang, Daniel C. Tessier, Daniel J. Schaid, Daniel O. Stram, Daniel W. Cramer, David E. Neal, Diana Eccles, Dieter Flesch‐Janys, Digna R. Velez Edwards, Dominika Wokozorczyk, Douglas A. Levine, Drakoulis Yannoukakos, Elinor J. Sawyer, Elisa V. Bandera, Elizabeth M. Poole, Ellen L. Goode, Э. К. Хуснутдинова, Estrid Høgdall, Fengju Song, Fiona Bruinsma, Florian Heitz, Francesmary Modugno, Freddie C. Hamdy, Fredrik Wiklund, Graham G. Giles, Håkan Olsson, Hans Wildiers, Hans-Ulrich Ulmer, Hardev Pandha, Harvey A. Risch, Hatef Darabi, Helga B. Salvesen, Heli Nevanlinna, Henrik Grönberg, Hermann Brenner, Hiltrud Brauch, Hoda Anton‐Culver, Honglin Song, Hui-Yi Lim, Iain A. McNeish, Ian Campbell, Ignace Vergote, Jacek Gronwald, Jan Lubiński, Janet L. Stanford, Javier Benı́tez, Jennifer A. Doherty, Jennifer B. Permuth, Jenny Chang‐Claude, Jenny Donovan, Joe Dennis, Joellen M. Schildkraut, Johanna Schleutker, John L. Hopper, Jolanta Kupryjańczyk, Jong Y. Park, Jonine D. Figueroa, Judith A. Clements, Julia A. Knight, Julian Peto, Julie M. Cunningham, Julio M. Pow‐Sang, Jyotsna Batra, Kamila Czene, Karen H. Lu, Kathleen Herkommer, Kay‐Tee Khaw, kConFab Investigators, Keitaro Matsuo, Kenneth Muir, Kenneth Offitt, Kexin Chen, Kirsten B. Moysich, Kristiina Aittomäki, Kunle Odunsi, Lambertus A. Kiemeney, Leon F.A.G. Massuger, Liesel M. FitzGerald, Linda S. Cook, Lisa Cannon‐Albright, Maartje J. Hooning, Malcolm C. Pike, Manjeet K. Bolla, Manuel Luedeke, Manuel R. Teixeira, Marc T. Goodman, Marjanka K. Schmidt, Marjorie J. Riggan, Markus Aly, Mary Anne Rossing, Matthias W. Beckmann, Matthieu Moisse, Maureen Sanderson, Melissa C. Southey, Michael E. Jones, Michael Lush, Michelle A.T. Hildebrandt, Ming‐Feng Hou, Minouk J. Schoemaker, Montserrat García‐Closas, Natalia Bogdanova, Nazneen Rahman, NBCS Investigators, Nhu D. Le, Nick Orr, Nicolas Wentzensen, Nora Pashayan, Paolo Peterlongo, Pascal Guénel, Paul Brennan, Paula Paulo, Penelope M. Webb, Per Broberg, Peter A. Fasching, Peter Devilee, Qin Wang, Qiuyin Cai, Qiyuan Li, Radka Kaneva, Ralf Bützow, Reidun Kristin Kopperud, Rita K. Schmutzler, Robert A. Stephenson, Robert J. MacInnis, Robert N. Hoover, Robert Winqvist, Roberta B. Ness, Roger L. Milne, Ruth C. Travis, Sara Benlloch, Sara H. Olson, Shannon K. McDonnell, Shelley S. Tworoger, Sofia Maia, Sonja I. Berndt, Soo Chin Lee, Soo‐Hwang Teo, Stephen N. Thibodeau, Stig E. Bojesen, Susan M. Gapstur, Susanne K. Kjær, Tanja Pejović, Teuvo L.J. Tammela, the GENICA Network, Thilo Dörk, Thomas Brüning, Tiina Wahlfors, Timothy J. Key, Todd L. Edwards, Usha Menon, Ute Hamann, Vanio Mitev, Veli‐Matti Kosma, Veronica Wendy Setiawan, Vessela Kristensen, Volker Arndt, Walther Vogel, Wei Zheng, Weiva Sieh, William J. Blot, Wojciech Kluźniak, Xiao‐Ou Shu, Yu‐Tang Gao, Fredrick R. Schumacher, Matthew L. Freedman, Andrew Berchuck, Alison M. Dunning, Jacques Simard, Christopher A. Haiman, Amanda B. Spurdle, Thomas A. Sellers, David J. Hunter, Brian E. Henderson, Peter Kraft, Stephen J. Chanock, Fergus J. Couch, Per Hall, Simon A. Gayther, Douglas F. Easton, Georgia Chenevix‐Trench, Rosalind A. Eeles, Paul D.P. Pharoah, Diether Lambrechts - Cancer Discovery 2016 cited by 214

UNLABELLED: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.