CpG Island Methylator Phenotype and Methylation of Wnt Pathway Genes Together Predict Survival in Patients with Colorectal Cancer
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Purpose: Dysregulation of the Wnt pathway is a crucial step in the tumorigenesis of colorectal cancer (CRC). This study aimed todetermine whether DNA methylation of Wnt pathway genes helps predict treatment response and survival in patients with metastaticor recurrent CRC. Materials and Methods: We retrospectively collected primary tumor tissues from 194 patients with metastatic or recurrent CRC. Pyrosequencing was used to examine the methylation of 10 CpG island loci in DNA extracted from formalin-fixed paraffin-embeddedspecimens. To elucidate the predictive role of DNA methylation markers, Kaplan-Meier survival estimation and Cox regressionwere performed for progression-free survival and overall survival (OS). Results: The methylation frequencies of the 10 genes analyzed (p16, p14, MINT1, MINT2, MINT31, hMLH1, DKK3, WNT5A,AXIN2, and TFAP2E) were 47.9%, 10.8%, 21.1%, 16.0%, 20.6%, 0.5%, 53.1%, 32.0%, 2.6%, and 2.1%, respectively. We divided patientsinto three groups based on the number of methylated genes (group 1, no methylation n=38; group 2, 1−2 methylationsn=92; group 3, 3 or more methylations n=64). Among patients treated with palliative chemotherapy (n=167), median OSs of groups1, 2, and 3 were 39.1, 39.7, and 29.1 months, respectively (log rank p=0.013). After adjustment, number of methylations was identifiedas an independent poor prognostic factor (0−2 methylated vs. ≥3 methylated: hazard ratio, 1.72; 95% confidence interval,1.16−2.56, p=0.007). Conclusion: This study suggests that methylation of Wnt pathway genes, in addition to known CpG island methylator phenotypemarkers, may help predict treatment outcome and survival in patients with CRC.
Abstract
Purpose: Dysregulation of the Wnt pathway is a crucial step in the tumorigenesis of colorectal cancer (CRC). This study aimed todetermine whether DNA methylation of Wnt pathway genes helps predict treatment response and survival in patients with metastaticor recurrent CRC. Materials and Methods: We retrospectively collected primary tumor tissues from 194 patients with metastatic or recurrent CRC. Pyrosequencing was used to examine the methylation of 10 CpG island loci in DNA extracted from formalin-fixed paraffin-embeddedspecimens. To elucidate the predictive role of DNA methylation markers, Kaplan-Meier survival estimation and Cox regressionwere performed for progression-free survival and overall survival (OS). Results: The methylation frequencies of the 10 genes analyzed (p16, p14, MINT1, MINT2, MINT31, hMLH1, DKK3, WNT5A,AXIN2, and TFAP2E) were 47.9%, 10.8%, 21.1%, 16.0%, 20.6%, 0.5%, 53.1%, 32.0%, 2.6%, and 2.1%, respectively. We divided patientsinto three groups based on the number of methylated genes (group 1, no methylation n=38; group 2, 1−2 methylationsn=92; group 3, 3 or more methylations n=64). Among patients treated with palliative chemotherapy (n=167), median OSs of groups1, 2, and 3 were 39.1, 39.7, and 29.1 months, respectively (log rank p=0.013). After adjustment, number of methylations was identifiedas an independent poor prognostic factor (0−2 methylated vs. ≥3 methylated: hazard ratio, 1.72; 95% confidence interval,1.16−2.56, p=0.007). Conclusion: This study suggests that methylation of Wnt pathway genes, in addition to known CpG island methylator phenotypemarkers, may help predict treatment outcome and survival in patients with CRC.
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