Identification Of A New Breast Cacner Risk Locus In A Genome-Wide Association Study Of Ashkenazi Jews

11005 Background: In the absence of BRCA mutations, variants of CHEK2, ATM, BRIP1 and PALB2, are associated with risk for breast cancer. Recently, two whole genome association studies (WGAS) implicated a locus near FGFR2 with a 1.2 fold increased risk of the disease. Methods: We performed a three-phase genome-wide association study (GWAS) using cases and controls from a genetically isolated population, Ashkenazi Jews (AJ), to identify loci associated with breast cancer risk. In the first phase, we compared allele frequencies of 150,080 single-nucleotide polymorphisms (SNPs) in 249 high-risk, BRCA1/2 mutation-negative AJ familial cases and 299 cancer-free AJ controls using chi square and the Cochran-Armitage trend tests. In the second phase, we genotyped 343 SNPs from 123 regions most significantly associated from stage 1, including 4 SNPs from the FGFR2 region, in 950 consecutive AJ breast cancer cases and 979 age-matched AJ controls. We replicated major associations in a third independent set of 243 AJ cases and 187 controls. Results: There was a significant allele P- value of association with AJ breast cancer in the FGFR2 region (P = 1.5 × 10-5, OR 1.26, 95% CI 1.13–1.40 at rs1078806 for all phases combined). In addition, we found a novel risk locus in a region of chromosome 6q (P = 2.9×10-8, OR 1.41, 95% CI 1.25–1.59). A major haplotype at the 6q locus conferred protection from disease, while the minor haplotype conferred risk. Approximately 7% of all breast cancer in this population is attributable to this risk factor, based on its high frequency and observed OR. Conclusions: These findings confirm FGFR2 as a locus associated with risk for breast cancer, and also indicate the presence of a novel locus on chromosome 6. There are several candidate genes at the 6q locus with homology to genes previously implicated in breast cancer pathogenesis. No significant financial relationships to disclose.