Frequent hypermethylation of MLH1 promoter in normal endometrium of patients with endometrial cancers.

Abstract:

:Silencing of the MLH1 gene by promoter hypermethylation is the mechanism underlying the microsatellite instability (MSI) phenotype in endometrial cancers. However, the profile of CpG methylation in a wide range of MLH1 promoters in endometrial cancers and in the normal endometrium is largely unknown. The present study investigates the region 700 bp upstream of MLH1 covering 48 CpG sites using bisulfite sequencing. Methylation status was classified as full (over 80% of CpGs are methylated), partial (10-80%) or nonmethylation (less than 10%). Of 56 endometrioid endometrial cancers, 16 (29%) were fully methylated, 14 (25%) were partially methylated and 26 (46%) were not methylated. Analyses of MLH1 by immunohistochemical means and of MSI revealed that the degree, rather than region-specific methylation of CpG islands is critical for decreased MLH1 expression and the MSI phenotype. Among 12 patients with methylated cancers, five (42%) patients contained methylated promoters in their normal endometria with profiles similar to those of cancer lesions, and these were associated with the MSI phenotype. In contrast, only one of 31 (3%) normal endometria from patients without endometrial malignancies harbored methylated promoters. These findings suggest that hypermethylation of the MLH1 promoter is frequent in the histologically normal endometrium adjacent to cancers, supporting the notion that hypermethylation of mismatch repair genes is the initial step that triggers various genetic events in endometrial carcinogenesis.

journal_name

Oncogene

journal_title

Oncogene

authors

Kanaya T,Kyo S,Maida Y,Yatabe N,Tanaka M,Nakamura M,Inoue M

doi

10.1038/sj.onc.1206365

subject

Has Abstract

pub_date

2003-04-17 00:00:00

pages

2352-60

issue

15

eissn

0950-9232

issn

1476-5594

pii

1206365

journal_volume

22

pub_type

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