Abstract 2779: A genome-wide analysis of more than 160,000 individuals identifies four novel pleiotropic risk loci shared between breast and ovarian cancer

Abstract

Abstract Background: Common variants in six genomic regions are known to confer susceptibility to both breast and ovarian cancer. We combined summary results from association studies of these two cancers to identify additional shared risk loci. Methods: We compiled an up-to-date list of the most significant variant at every independent locus known to be associated with ovarian (n = 18) and/or breast (n = 92) cancer risk at genome-wide significance (P < 5×10-8) in women of European ancestry. Subtype specific and unpublished variants were included. We evaluated association at each variant for the other cancer using summary results from the OCAC and BCAC data sets (cases/controls: ovarian ∼15K/31K and breast ∼63K/61K). Each data set was restricted to European ancestry samples, had been imputed into the 1000 Genomes panel, and comprised summary statistics from meta-analysis of GWAS and case-control studies genotyped for ∼200K variants on the iCOGS custom array. We considered the evaluated associations significant at a threshold P-value < 4.6×10-4 after Bonferroni correction for multiple comparisons. In a separate approach, we combined results for all variants with P < 10-3 in both data sets using fixed effects inverse variance meta-analysis. We also conducted a subtype specific meta-analysis by combining results for serous ovarian and estrogen receptor (ER)-negative breast cancer risk. Variants identified within 1 Mb of known risk regions in each data set were excluded and only novel findings are reported here. Results: One ovarian cancer risk variant was also associated with breast cancer risk in the same direction as its known ovarian association at P < 4.6×10-4: rs635634 at 9q34 (P(breast) = 8.1×10-7). The meta-analyses identified three additional risk loci at genome-wide significance. Rs10820599 at 9q31 (P = 4.1×10-9) and rs8037137 at 15q26 (P = 1.9×10-10) were associated with overall ovarian and breast cancer risk and rs201308915 at 2p23 (P = 3.2×10-8) was associated specifically with serous ovarian and ER-negative breast cancer risk. None of the variants demonstrated statistical evidence of heterogeneity in effect between cancers. Tissue-specific annotation, quantitative trait locus and pathway analyses of these loci to identify potential pleiotropic functional mechanisms are ongoing. Conclusion: These results confirm the pleiotropic effects of alleles at four new loci on breast and ovarian cancer susceptibility. Three of them have not previously been associated at genome-wide significance with risk of either cancer. Future cross-cancer analysis based on even larger data sets and incorporating other hormone-related cancers are likely to yield further insights into the shared genetic basis of these common cancers. Citation Format: Siddhartha Kar, Kyriaki Michailidou, Jonathan Tyrer, Deborah Thompson, Diether Lambrechts, Ovarian Cancer Association Consortium (OCAC) and Breast Cancer Association Consortium (BCAC). A genome-wide analysis of more than 160,000 individuals identifies four novel pleiotropic risk loci shared between breast and ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2779. doi:10.1158/1538-7445.AM2015-2779