Abstract
Epigenetic alterations of specific genes have been reported to be related to colorectal cancer (CRC) transformation and would also appear to be involved in the early stages of colorectal carcinogenesis. Little data are available on the role of these alterations in determining a different risk of colorectal lesion recurrence. The aim of the present study was to verify whether epigenetic alterations present in pre-neoplastic colorectal lesions detected by colonoscopy can predict disease recurrence. A retrospective series of 78 adenomas were collected and classified as low (35) or high-risk (43) for recurrence according to National Comprehensive Cancer Network guidelines. Methylation alterations were analyzed by the methylation-specific multiplex ligation probe assay (MS-MLPA) which is capable of quantifying methylation levels simultaneously in 24 different gene promoters. MS-MLPA results were confirmed by pyrosequencing and immunohistochemistry. Higher levels of methylation were associated with disease recurrence. In particular, MLH1, ATM and FHIT gene promoters were found to be significantly hypermethylated in recurring adenomas. Unconditional logistic regression analysis used to evaluate the relative risk (RR) of recurrence showed that FHIT and MLH1 were independent variables with an RR of 35.30 (95% CI 4.15-300.06, P = 0.001) and 17.68 (95% CI 1.91-163.54, P = 0.011), respectively. Histopathological classification does not permit an accurate evaluation of the risk of recurrence of colorectal lesions. Conversely, results from our methylation analysis suggest that a classification based on molecular parameters could help to define the mechanisms involved in carcinogenesis and prove an effective method for identifying patients at high risk of recurrence.
Highlights
Epigenetic alterations of specific genes have been reported to be related to colorectal cancer (CRC) transformation and would appear to be involved in the early stages of colorectal carcinogenesis
Lesions were classified as adenomas at low risk (3 tubular polyps with a diameter < 1 cm) or high risk of recurrence according to National Comprehensive Cancer Network guidelines
methylation-specific multiplex ligation probe assay (MS-MLPA) analysis Tissue specimens of adenomas from 78 patients were collected for methylation status analysis (Table 2)
Summary
Epigenetic alterations of specific genes have been reported to be related to colorectal cancer (CRC) transformation and would appear to be involved in the early stages of colorectal carcinogenesis. Little data are available on the role of these alterations in determining a different risk of colorectal lesion recurrence. The aim of the present study was to verify whether epigenetic alterations present in pre-neoplastic colorectal lesions detected by colonoscopy can predict disease recurrence. Colorectal cancer (CRC), a disease arising from complex and heterogeneous etiological factors and pathogenetic mechanisms, develops in a multi-step manner from normal epithelium, through a pre-malignant lesion (adenoma), into a malignant lesion (carcinoma) [1]. Different molecular mechanisms seem to be related to CRC development. Epigenetic alterations have gained recognition as a key mechanism in carcinogenesis. Hypermethylation of CpG islands present in gene promoter sequences leads to the inactivation of tumor suppressor genes, working in a different way with respect to genetic mutations [8,9]
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