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

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Siddhartha P Kar, Jonathan Beesley, Ali Amin Al Olama, Kyriaki Michailidou, Jonathan Tyrer, ZSofia Kote-Jarai, Kate Lawrenson, Sara Lindstrom, Susan J Ramus, Deborah J Thompson, Adam S Kibel, Agnieszka Dansonka-Mieszkowska, Agnieszka Michael, Aida K Dieffenbach, Aleksandra Gentry-Maharaj, Alice S Whittemore, Alicja Wolk, Alvaro Monteiro, Ana Peixoto, Andrzej Kierzek & 31 others Angela Cox, Anja Rudolph, Anna Gonzalez-Neira, Anna H Wu, Annika Lindblom, Anthony Swerdlow, Argyrios Ziogas, Arif B Ekici, Barbara Burwinkel, Beth Y Karlan, Børge G Nordestgaard, Carl Blomqvist, Catherine Phelan, Catriona McLean, Celeste Leigh Pearce, Celine Vachon, Cezary Cybulski, Chavdar Slavov, Christa Stegmaier, Christiane Maier, Christine B Ambrosone, Claus K Høgdall, Craig C Teerlink, Daehee Kang, Daniel C Tessier, Daniel J Schaid, Daniel O Stram, Estrid Høgdall, Stig E Bojesen, Susanne Krüger Kjær, ABCTB Investigators

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.

Original languageEnglish
JournalCancer Discovery
Volume6
Issue number9
Pages (from-to)1052-67
Number of pages16
ISSN2159-8274
DOIs
Publication statusPublished - Sep 2016

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  • Journal Article

ID: 167585371