Purpose: Several single nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified through genome-wide association studies (GWAS). We investigated whether eight risk SNPs identified in GWAS were associated with breast cancer disease-free survival (DFS) and overall survival (OS).
Methods: A cohort of 739 white women with early-stage breast carcinoma was genotyped for eight GWAS-identified SNPs (rs2981582, rs1219648, rs3803662, rs12443621, rs8051542, rs999737, rs6504950, rs4973768), using Illumina GoldenGate platform. The relationships between SNPs and breast cancer outcomes were evaluated using univariate and multivariate Cox proportional hazard regression models. The cumulative effects of SNPs were assessed by computing the number of at-risk-alleles based on the results from the univariate analyses. In addition, we explored higher-order interactions between clinical variables and SNPs using classification and regression tree (CART) analysis.
Results: Four SNPs (rs2981582, rs1219648, rs12443621 and rs6504950) were significantly associated with OS using univariate Cox proportional hazard regression analysis (P≤0.1) and there was no association with DFS. In multivariate model adjusted for age, hormonal status, clinical stage, and treatment, rs12443621 (16q12) and rs6504950 (17q23) polymorphisms remained as independent prognostic markers for OS. Compared with the GG/AG reference group, homozygous carriers of minor A allele for rs12443621 and rs6504950 had an increased risk for death (HR:1.38, 95% CI:1.01 to 1.86; P=0.04, and HR:1.80, 95% CI:1.18 to 2.77; P=0.007, respectively). In multivariate analysis, a higher risk for death was found in the sub-cohort of patients harboring 3–4 at-risk-alleles of the GWAS SNPs compared to patients carrying ≤2 at-risk-alleles (HR:1.5, 95% CI:1.14 to 1.85; P=0.002). In CART modeling, women with stage 2 breast cancer who did not receive chemotherapy and were carries of the AA genotype for rs6504950 had the highest risk for death (HR:10.0, 95% CI:3.47 to 28.78).
Conclusion: SNPs in previously identified breast cancer risk susceptibility loci, rs12443621 (16q12) and rs6504950 (17q23), were also found to be independent prognostic markers for OS in breast cancer patients. The precise molecular mechanisms through which these SNPs influence clinical outcomes remain to be determined.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A61.