<i>IGFBP3</i> Methylation Is a Novel Diagnostic and Predictive Biomarker in Colorectal Cancer

<div><p>Background and Aim</p><p>Aberrant 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.</p><p>Patients and Methods</p><p>Methylation status of the <i>SEPT9, TWIST1, IGFBP3, GAS7, ALX4 and miR137</i> genes was studied by quantitative bisulfite pyrosequencing in a population-based cohort of 425 CRC patients.</p><p>Results</p><p>Methylation 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 <i>miR137</i> (86.7%) and <i>IGFBP3</i> (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 <i>IGFBP3</i> 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 <i>IGFBP3</i> methylation do not benefit from adjuvant 5FU-based chemotherapy.</p><p>Conclusion</p><p>By analyzing a large, population-based CRC cohort, we demonstrate the potential clinical significance of <i>miR137</i> and <i>IGFBP3</i> hypermethylation as promising diagnostic biomarkers in CRC. Our data also revealed that <i>IGFBP3 hyper</i>methylation may serve as an independent prognostic and predictive biomarker in stage II and III CRC patients.</p>