Promoter methylation of tumor suppressor genes in pre-neoplastic lesions; potential marker of disease recurrence

Abstract

BackgroundEpigenetic 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.MethodsA 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.ResultsHigher 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.ConclusionsHistopathological 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.

Genome‐wide DNA methylation analysis of colorectal adenomas with and without recurrence reveals an association between cytosine‐phosphate‐guanine methylation and histological subtypes

“…This seems contradictory to the findings of Rengucci and colleagues who identified the promoters of MLH1, ATM, and FHIT to be hypermethylated in adenomas with high recurrence risk. 36 However, this risk assessment was based on assumptions and not on real clinical follow up data, which could explain the discrepancies to our findings.…”

Clinical significance of protocadherin 8 (PCDH8) promoter methylation in non-muscle invasive bladder cancer

“…In recent years, more and more researchers are interested in the aberrant methylation of different genes in bladder cancer for some reasons [9,10,26]. Firstly, aberrant methylation in the promoter regions of the tumor suppressor genes at CPG islands has been recognized as one of the hallmarks of human cancers and associated with silence of gene expression, which may be used as potential biomarker in human cancers [27][28][29][30][31]. Secondly, DNA methylation can be reversed by demethylating agents, which may used as effective therapeutic target.…”

Hypermethylation of tumor suppressor genes in gastric cancer: associations with demographic and clinicopathological characteristics

“…Experimental procedures of the MLPA, data analysis and cutoff selection were carried out by the manufacturer's instructions. 20 At every turn, reference samples isolated from a healthy stomach tissue and 3 cancer tissues were worked together. Methylated regions were determined by comparison of results with reference samples.…”