Comprehensive analysis of colorectal cancer-risk loci and survival outcome: A prognostic role for CDH1 variants.

Purpose: Genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at 83 loci associated with colorectal cancer (CRC) risk in European populations. Because germline variation can also influence patient outcome, we studied the relationship between these SNPs and CRC survivorship.
Experimental Design: For the 83 risk loci, 10 lead SNPs were directly genotyped, 72 were imputed and 1 was not genotyped nor imputed, in 1948 unrelated patients with advanced CRC from the clinical trials COIN and COIN-B (oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab). A Cox survival model was used for each variant, and variants classified by pathway, adjusting for known prognostic factors. We imposed a Bonferroni threshold of P = 6.6 × 10 ^-4 for multiple testing. We carried out meta-analyses of published risk SNPs associated with survival.
Results: Univariate analysis identified six SNPs associated with overall survival (OS) (P < 0.05); however, only rs9939049 in CDH1 remained significant beyond the Bonferroni threshold (Hazard Ratio [HR] 1.44, 95% Confidence Intervals [CI]: 1.21-1.71, P = 5.0 × 10 ^-5 ). Fine mapping showed that rs12597188 was the most significant SNP at this locus and remained significant after adjustment for known prognostic factors beyond multiple testing thresholds (HR 1.23, 95% CI: 1.13-1.34, P = 1.9 × 10 ^-6 ). rs12597188 was also associated with poor response to therapy (OR 0.61, 95% CI: 0.42-0.87, P = 6.6 × 10 ^-3 ). No combinations of SNPs within pathways were more significantly associated with survival compared with single variants alone, and no other risk SNPs were associated with survival in meta-analyses.
Conclusions: The CRC susceptibility SNP rs9939049 in CDH1 influences patient survival and warrants further evaluation as a prognostic biomarker.
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