Abstract
Changes in DNA methylation, whether hypo- or hypermethylation, have been shown to be associated with the progression of colorectal cancer. Methylation changes substantially in the progression from normal mucosa to adenoma and to carcinoma. This phenomenon has not been studied extensively and studies have been restricted to individual CpG islands, rather than taking a whole-genome approach. We aimed to study genome-wide methylation changes in colorectal cancer. We obtained 10 fresh-frozen normal tissue–cancer sample pairs, and five fresh-frozen adenoma samples. These were run on the lllumina HumanMethylation27 whole-genome methylation analysis system. Differential methylation between normal tissue, adenoma and carcinoma was analysed using Bayesian regression modelling, gene set enrichment analysis (GSEA) and hierarchical clustering (HC). The highest-rated individual gene for differential methylation in carcinomas versus normal tissue and adenomas versus normal tissue was GRASP (padjusted = 1.59 × 10–5, BF = 12.62, padjusted = 1.68 × 10–6, BF = 14.53). The highest-rated gene when comparing carcinomas versus adenomas was ATM (padjusted = 2.0 × 10–4, BF = 10.17). Hierarchical clustering demonstrated poor clustering by the CIMP criteria for methylation. GSEA demonstrated methylation changes in the Netrin–DCC and SLIT–ROBO pathways. Widespread changes in DNA methylation are seen in the transition from adenoma to carcinoma. The finding that GRASP, which encodes the general receptor for phosphoinositide 1-associated scaffold protein, was differentially methylated in colorectal cancer is interesting. This may be a potential biomarker for colorectal cancer. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Highlights
Epigenetic modification of DNA has been increasingly recognized as performing an important role in carcinogenesis
In contrast comparing normal tissue with carcinoma, there was a shift towards increased methylation in promoter regions in the latter, an observation confirmed by the larger proportion of genes that were methylated in carcinomas versus adenomas
These results suggest that the bulk of promoter methylation occurs around the time of transition from colorectal adenoma to carcinoma
Summary
Epigenetic modification of DNA has been increasingly recognized as performing an important role in carcinogenesis. There are surprisingly few studies of genome-wide methylation and its effects in colorectal cancer (CRC). Initial studies of gene-specific promoter methylation [1] described the phenomenon of the CpG island phenotype (CIMP), in which multiple tumour suppressor genes, such as CDKN2A and MLH1 , were aberrantly methylated at their promoter regions. CIMP tumours are known to have distinct clinical and pathological characteristics. These include [2] high rates of microsatellite instability (MSI) and BRAF mutations, as well as being predominantly in the right side of the colon. Extensive work has been carried out to investigate the characteristics of CIMP tumours. Ogino et al [2]
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