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.

Publication Type:

Journal Article

Source:

Clinical cancer research : an official journal of the American Association for Cancer Research (2015)

Abstract:

Purpose Genome wide association studies have identified numerous loci associated with colorectal cancer (CRC) 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 CRC. Experimental Design In our training phase, we analysed 20 CRC-risk single nucleotide polymorphisms (SNPs) from 14 genome wide associated loci, for their effects on survival in 2083 patients with advanced CRC. A Cox survival model was used, stratified for treatment, adjusted for known prognostic factors and corrected for multiple testing. Three SNPs were subsequently analysed in an independent validation cohort of 5552 CRC patients. A validated SNP was analysed 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%CI 1.20-1.71, P=5.8x10-5; validation phase HR=1.18, 95%CI 1.01-1.37, P=3.2x10-2; combined HR=1.28 95%CI 1.14-1.43, P=2.2x10-5). This effect was independent of known prognostic factors, and was significant amongst patients with stage 4 disease (P=2.7x10-5). rs9929218 was also associated with poor response to chemotherapy (P=3.9x10-4). Conclusions We demonstrate the potential of common inherited genetic variants to inform patient outcome and show that rs9929218 identifies ~8% of CRC patients with poor prognosis. rs9929218 may affect CDH1 expression and E-cadherin plays a role in epithelial-mesenchymal transition providing a mechanism underlying its prognostic potential.