Genome-wide Meta-analyses of Breast, Ovarian and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by At Least Two Cancer Types

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

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