Abstract
Background and AimAberrant hypermethylation of cancer-related genes has emerged as a promising strategy for the development of diagnostic, prognostic and predictive biomarkers in human cancer, including colorectal cancer (CRC). The aim of this study was to perform a systematic and comprehensive analysis of a panel of CRC-specific genes as potential diagnostic, prognostic and predictive biomarkers in a large, population-based CRC cohort.Patients and MethodsMethylation status of the SEPT9, TWIST1, IGFBP3, GAS7, ALX4 and miR137 genes was studied by quantitative bisulfite pyrosequencing in a population-based cohort of 425 CRC patients.ResultsMethylation levels of all genes analyzed were significantly higher in tumor tissues compared to normal mucosa (p<0.0001); however, cancer-associated hypermethylation was most frequently observed for miR137 (86.7%) and IGFBP3 (83%) in CRC patients. Methylation analysis using the combination of these two genes demonstrated greatest accuracy for the identification of colonic tumors (sensitivity 95.5%; specificity 90.5%). Low levels of IGFBP3 promoter methylation emerged as an independent risk factor for predicting poor disease free survival in stage II and III CRC patients (HR = 0.49, 95% CI: 0.28–0.85, p = 0.01). Our results also suggest that stage II & III CRC patients with high levels of IGFBP3 methylation do not benefit from adjuvant 5FU-based chemotherapy.ConclusionBy analyzing a large, population-based CRC cohort, we demonstrate the potential clinical significance of miR137 and IGFBP3 hypermethylation as promising diagnostic biomarkers in CRC. Our data also revealed that IGFBP3 hypermethylation may serve as an independent prognostic and predictive biomarker in stage II and III CRC patients.
Highlights
Colorectal cancer (CRC) is one of the most common cancers in Western countries, and is the second leading cause of cancerrelated deaths in adults [1]
We found that 35/425 (8.2%) colorectal cancer (CRC) were Microsatellite Instability (MSI), 90/303 (29.7%) were CpG Island Methylator Phenotype (CIMP)-positive, and 21/191 (10.9%) harbored a somatic V600E mutation in the BRAF gene
The CIMP-positive phenotype was more frequently associated with MSI and the presence of BRAF V600E mutation (22.3% vs. 2.3%, p,0.0001 for the MSI phenotype, and 31% vs. 1.5%, p,0.0001 for the BRAF V600E mutation)
Summary
Colorectal cancer (CRC) is one of the most common cancers in Western countries, and is the second leading cause of cancerrelated deaths in adults [1]. Epigenetic alterations, DNA hypermethylation, can be used for the early detection of premalignant lesions, including adenomatous polyps in the colon, and is present in the non-neoplastic tissues adjacent to adenomatous polyps and cancers in the colon [5,6]. In addition to their use as diagnostic biomarkers, epigenetic changes show promise as determinants of cancer prognosis, as well as biomarkers for response to specific chemotherapies [7,8]. The aim of this study was to perform a systematic and comprehensive analysis of a panel of CRC-specific genes as potential diagnostic, prognostic and predictive biomarkers in a large, population-based CRC cohort
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