Accumulation of Promoter Methylation Suggests Epigenetic Progression in Squamous Cell Carcinoma of the Esophagus

Abstract

Purpose: Squamous esophageal cancer is common in non-Western countries and has a welldefined progression of preinvasive dysplasia leading to invasive squamous cell carcinoma. We examined the changes in promoter region methylation occurring during neoplastic progression. Experimental Design: The frequency of epigenetic changes in the promoter region of 14 genes epigenetically silenced in other cancers was determined and examined the most frequent changes in dysplastic lesions using methylation-specific PCR. Invasive squamous carcinomas, low to high grade dysplasia, and normal esophagus were then examined for methylation changes in the promoter region of each of the eight most commonly methylated genes. Results: Methylation was most frequent for CDKN2A/p16INK4a (52%) but was also common for O 6 -methylguanine-DNA methyltransferase, E-cadherin (CDH1), and retinoic acid receptor h2. Methylation at individual genes increased in frequency from normal to invasive cancer. Methylation of MLH1 was associated with microsatellite instability in most cases. The number of genes methylated in individual lesions increased as cellular atypia increased. In individual patients, cancers adjacent to dysplasia had the same epigenetic alterations as the less advanced lesions but often had additional methylation of other genes. Conclusions: These findings suggest that epigenetic progression parallels the histologic changes observed in the progression of squamous carcinoma of the esophagus.

Revisit of Field Cancerization in Squamous Cell Carcinoma of Upper Aerodigestive Tract: Better Risk Assessment with Epigenetic Markers

“…Mutations of p53 or p53 oncoprotein are relatively late events in carcinogenesis (42,43), so, despite their biological plausibility as cancer predictors, they are insufficient for risk assessments for SCC in the UADT. Because aberrant DNA methylation usually precedes neoplastic transformation, qualitative studies have suggested that the presence of methylated genes may increase in a sequence from normal mucosa to precursor lesions to SCC (44)(45)(46). Our study further found that this phenomenon is quantitative for individual gene markers.…”

Hypermethylation of multiple tumor-related genes associated with DMNT3b up-regulation served as a biomarker for early diagnosis of esophageal squamous cell carcinoma

“…As disruption of processes involved in programmed cell death is a common feature of human cancers, it is significant that inactivation of DAPK by promoter methylation has been described in esophageal cancer. [20][21][22] Retinoids regulate the growth, differentiation and apoptosis of premalignant and malignant cells during carcinogenesis. RAR-β, which acts as retinoic acid-dependent transcriptional activators, predominantly mediated the effects of retinoids.…”

936 Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer

“…37,48,49 In our analysis of NMIBC it remains unclear whether the increase in frequency and/or mean levels of methylation in the more aggressive tumors represents a more rapid accumulation of epigenetic changes during tumor progression, or reflects distinct epigenetic pathways of tumor development and outgrowth. 50,51 Our findings may therefore reflect either of the described scenarios in the more aggressive (high-grade) tumors and suggests that these tumors are either consequent to progression from low-intermediategrade tumors, or are the progeny of aberrations in distinct epigenetic pathways within these NMIBC subtypes. Moreover, the identification of different patterns of methylation between tumors represents an important area for future investigation.…”