Analyses of 7,635 Patients with Colorectal Cancer Using Independent Training and Validation Cohorts Show That rs9929218 in CDH1 Is a Prognostic Marker of Survival.
Smith CG., Fisher D., Harris R., Maughan TS., Phipps AI., Richman S., Seymour M., Tomlinson I., Rosmarin D., Kerr D., Chan AT., Peters U., Newcomb PA., Idziaszczyk S., West H., Meade A., Kaplan R., Cheadle JP.
PURPOSE: Genome-wide association studies have identified numerous loci associated with colorectal cancer risk. Several of these have also been associated with patient survival, although none have been validated. Here, we used large independent training and validation cohorts to identify robust prognostic biomarkers for colorectal cancer. EXPERIMENTAL DESIGN: In our training phase, we analyzed 20 colorectal cancer-risk SNPs from 14 genome-wide associated loci, for their effects on survival in 2,083 patients with advanced colorectal cancer. A Cox survival model was used, stratified for treatment, adjusted for known prognostic factors, and corrected for multiple testing. Three SNPs were subsequently analyzed in an independent validation cohort of 5,552 colorectal cancer patients. A validated SNP was analyzed by disease stage and response to treatment. RESULTS: Three variants associated with survival in the training phase; however, only rs9929218 at 16q22 (intron 2 of CDH1, encoding E-cadherin) was significant in the validation phase. Patients homozygous for the minor allele (AA genotype) had worse survival (training phase HR, 1.43; 95% confidence intervals; CI, 1.20-1.71, P = 5.8 × 10(-5); validation phase HR, 1.18; 95% CI, 1.01-1.37, P = 3.2 × 10(-2); combined HR, 1.28; 95% CI, 1.14-1.43, P = 2.2 × 10(-5)). This effect was independent of known prognostic factors, and was significant amongst patients with stage IV disease (P = 2.7 × 10(-5)). rs9929218 was also associated with poor response to chemotherapy (P = 3.9 × 10(-4)). CONCLUSIONS: We demonstrate the potential of common inherited genetic variants to inform patient outcome and show that rs9929218 identifies approximately 8% of colorectal cancer patients with poor prognosis. rs9929218 may affect CDH1 expression and E-cadherin plays a role in epithelial-to-mesenchymal transition providing a mechanism underlying its prognostic potential. Clin Cancer Res; 21(15); 3453-61. ©2015 AACR.