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

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 &lt; 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 &lt; 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