biostudies-literatureSmith CGCancer Research UKNIA NIH HHSMedical Research CouncilNHLBI NIH HHSNCI NIH HHSTenovus Cancer CareWellcome TrustNIH HHSWHI NIH HHS3453-61https://www.ebi.ac.uk/biostudies/studies/S-EPMC4526710biostudies-literatureUnknown21(15)<h4>Purpose</h4>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.<h4>Experimental design</h4>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.<h4>Results</h4>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)).<h4>Conclusions</h4>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.Clinical cancer research : an official journal of the American Association for Cancer ResearchAnalyses of 7,635 Patients with Colorectal Cancer Using Independent Training and Validation Cohorts Show That rs9929218 in CDH1 Is a Prognostic Marker of Survival.PMC4526710U01 CA137088K05 CA154337P01 CA087969K05 CA152715A5427A4850090532K07 CA172298HHSN268201100003CUM1 CA167552N01AG1210616459HHSN268201100001IP01 CA055075HHSN268201100003I090532/Z/09/ZR01 CA059045S10 OD020069HHSN268201100001CMC_UU_12023/20R01 CA137178P30 CA01570420240R01 CA042182MC_UU_12023/3A4886HHSN268201100004CPhD2009/L27HHSN268201100002IHHSN271201100004CHHSN268201100004IMC_U122861325P50 CA127003HHSN268201100002CHHSN268201100046CMaughan TSKaplan RChan ATHarris RRichman SSmith CGTomlinson IWest HFisher DPhipps AIRosmarin DIdziaszczyk SMeade APeters UCheadle JPSeymour MNewcomb PAKerr DfalseAnalyses of 7,635 Patients with Colorectal Cancer Using Independent Training and Validation Cohorts Show That rs9929218 in CDH1 Is a Prognostic Marker of Survival.<h4>Purpose</h4>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.<h4>Experimental design</h4>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.<h4>Results</h4>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)).<h4>Conclusions</h4>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.2015-01-01T00:00:00Z2015 Aug2024-11-12T23:21:34.935Z2019-03-26T23:48:15ZS-EPMC45267102587308710.1158/1078-0432.ccr-14-313610.1158/1078-0432.CCR-14-3136