FGFR2 is a breast cancer susceptibility gene in Israeli populations Free

B74

We validated genome-wide association scan (GWAS) findings of FGFR2 as a risk factor for breast cancer and estimated the contribution of FGFR2 polymorphisms to breast cancer risk in diverse ethnic groups within the Jewish and other Middle Eastern populations. Taking advantage of a large ongoing, population-based case-control study of the molecular and environmental etiology of breast cancer in Israel, we genotyped four FGFR2 SNPs (rs11200014, rs2981579, rs1219648, rs2420946) in intron 2 and tested for association of these SNP and their haplotypes with breast cancer risk in the series of 1529 women with breast cancer and 1528 controls.
 >We found evidence of significant associations between risk of breast cancer and all four studied SNPs in FGFR2 (p for trend for all SNPs are <0.0001). The analysis in different ethnic groups showed significant association of all four studied SNPs with breast cancer risk in Ashkenazi and Sephardi Jews (p for trend for all SNPs are <0.01), with a similar, but not significant trend in Arabs. There was no significant effect modification of the association between FGFR2 SNPs and risk of breast cancer by age at diagnosis, first degree family history of breast cancer, or ethnicity.
 >Haplotype analysis identified four common haplotypes (five in Sephardi Jews and Arabs) with frequencies >0.01. The common AAGT haplotype, previously demonstrated as a risk haplotype in white non-Hispanic women was significantly associated with breast cancer risk in Ashkenazi (OR=1.22, 95%CI=1.04-1.42, p=0.0125) and Sephardi Jews (OR=1.42, 95%CI=1.14-1.76, p=0.015) compared to the reference GGAC haplotype. A second low frequency haplotype (AAAC) was significantly associated with breast cancer risk in Sephardi Jews only (OR=1.98, 95%CI=1.16-3.36, p=0.0121). This haplotype (AAAC) was about 4 times more frequent in Sephardi Jews and Arabs than in Ashkenazi Jews. The reference GGAC haplotype was the most frequent in Ashkenazi Jews and Arabs, but not in Sephardi Jews. None of the haplotypes showed a significant association with breast cancer risk in Arabs, although power is limited in this group and the direction of the associations was consistent with those observed in other populations. The GAGT haplotype, equally frequent among Sephardi Jews and Arabs (0.016 and 0.019 respectively), but less frequent in Ashkenazi Jews (0.008), was also significantly associated with risk of breast cancer.
 >The present study shows that FGFR2 is a breast cancer susceptibility gene in Ashkenazi and Sephardi Jews and appears to confer modest risk in Arab populations as well. The population attributable risk for rs1219648 is 16% for Ashkenazi and 22% for Sephardi Jews, and could be as high as 12% in Arabs. Our findings may help to identify FGFR2 causal variants for breast cancer.