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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, Christopher G., Fisher, David, Harris, Rebecca, Maughan, Timothy S., Phipps, Amanda I., Richman, Susan, Seymour, Matthew, Tomlinson, Ian, Rosmarin, Dan, Kerr, David, Chan, Andrew T., Peters, Ulrike, Newcombe, Polly A., Idziaszczyk, Shelley, West, Hannah, Meade, Angela, Kaplan, Richard and Cheadle, Jeremy P. 2015. 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. Clinical Cancer Research 21 (15) , pp. 3453-3461. 10.1158/1078-0432.CCR-14-3136

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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% con- fidence intervals; CI, 1.20–1.71, P ¼ 5.8 105 ; validation phase HR, 1.18; 95% CI, 1.01–1.37, P ¼ 3.2 102 ; combined HR, 1.28; 95% CI, 1.14–1.43, P ¼ 2.2 105 ). This effect was independent of known prognostic factors, and was significant amongst patients with stage IV disease (P ¼ 2.7 105 ). rs9929218 was also associated with poor response to chemotherapy (P ¼ 3.9 104 ). 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 affectCDH1 expression and E-cadherin plays a role in epithelial-to-mesenchymal transition providing a mechanism underlying its prognostic potential.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: American Association for Cancer Research
ISSN: 1078-0432
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 6 April 2015
Last Modified: 19 Jan 2021 12:14

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