Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer

Wong, Justin J.-L., Hawkins, Nicholas J., Ward, Robyn L. and Hitchins, Megan P. (2011) Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer. Modern Pathology, 24 3: 396-411. doi:10.1038/modpathol.2010.212


Author Wong, Justin J.-L.
Hawkins, Nicholas J.
Ward, Robyn L.
Hitchins, Megan P.
Title Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer
Formatted title
Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer
Journal name Modern Pathology   Check publisher's open access policy
ISSN 0893-3952
1530-0285
Publication date 2011-01-01
Year available 2010
Sub-type Article (original research)
DOI 10.1038/modpathol.2010.212
Open Access Status Not Open Access
Volume 24
Issue 3
Start page 396
End page 411
Total pages 16
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Abstract Epigenetic silencing of cancer-related genes by promoter methylation is a frequent event in sporadic colorectal cancer. The CpG island methylator phenotype (CIMP), in which discrete genes throughout the genome are simultaneously methylated, and long-range epigenetic silencing, whereby multiple genes within contiguous chromosomal regions are methylated, have been described in subsets of colorectal cancer. We previously reported the concurrent methylation of the mismatch repair gene MLH1 with a cluster of flanking genes in chromosome region 3p22 in sporadic colorectal carcinoma exhibiting microsatellite instability and the BRAF V600E mutation. Herein, we aimed to determine whether methylation of MLH1 and neighbouring 3p22 genes, singly or concomitantly, correlate with the germline c.-93GA SNP within the MLH1 promoter, CIMP and other clinicopathological and molecular features of the tumours. By studying a cohort of 946 sporadic colorectal cancer cases, we show a strong association between concordant methylation of 3 of five 3p22 genes with CIMP and the BRAF V600E mutation (P0.001). These associations were independent of microsatellite instability, as concomitant methylation of 3p22 genes other than MLH1 was found in microsatellite stable cancers. These findings show that long-range epigenetic silencing across 3p22 occurs in the context of CIMP and the BRAF V600E mutation, and only gives rise to microsatellite instability when this process encompasses MLH1. Furthermore, the strong relationship between long-range epigenetic silencing of 3p22 and CIMP provides further evidence that these two purportedly distinct epigenetic phenotypes represent a single entity with a common aetiology. Low-level methylation of MLH1 and flanking 3p22 genes, as well as the BRAF V600E mutation, were detected in the apparently normal colonic mucosa of a small number of cases whose tumours showed a similar molecular profile, suggesting that these concurring genetic and epigenetic events can occur as a field defect in neoplastic development.
Keyword CIMP
Colorectal cancer
Long-range epigenetic silencing
Methylation
MLH1
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Office of the Vice-Chancellor
School of Medicine Publications
 
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