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

Oncogene volume 22, pages 2352–2360 (2003)Cite this article

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 Q1not methylated. Analyses of MLH1 by immunohistochemical means and of MSI revealed that the Q2degree, 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.

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Acknowledgements

We are grateful to Dr Miki Nakajima, Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University for helpful discussions and suggestions. This study was supported in part by Foundation for Promotion of Cancer Research, Kanzawa Medical Research Foundation and a Grant-in Aid for the Second Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health and Welfare, Japan.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Kanazawa University School of Medicine, 13-1, Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan

    Taro Kanaya, Satoru Kyo, Yoshiko Maida, Noriyuki Yatabe, Masaaki Tanaka, Mitsuhiro Nakamura & Masaki Inoue

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  1. Taro Kanaya
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  2. Satoru Kyo
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Correspondence to Satoru Kyo.

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Kanaya, T., Kyo, S., Maida, Y. et al. Frequent hypermethylation of MLH1 promoter in normal endometrium of patients with endometrial cancers. Oncogene 22, 2352–2360 (2003). https://doi.org/10.1038/sj.onc.1206365

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