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Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma–carcinoma sequence

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Abstract

Purpose

Epigenetic silencing of the DNA mismatch repair genes has been poorly described in colorectal carcinomas showing the classic adenoma–carcinoma pathway of carcinogenesis. The aim of this study was to investigate the methylation status of MutL homolog 1 (hMLH1), MutS homolog 2 (hMSH2), and O-6-methylguanine-DNA methyltransferase (MGMT) in a series of colorectal carcinomas that contain both adenomas and carcinomas.

Methods

Promoter methylation of hMLH1, hMSH2, and MGMT was evaluated in normal mucosa, adenoma, and carcinoma samples from 112 colorectal cancer patients. Methylation was assessed by bisulfite modification and methylation-specific PCR. Expression of the gene products was also examined by immunohistochemistry.

Results

Of the 112 adenomas, methylation was detected for hMLH1 (2, 1.8%), hMSH2 (9, 8.0%), and MGMT (38, 33.9%). In the carcinoma samples, methylation was seen in hMLH1 (2, 1.8%), hMSH2 (15, 13.4%), and MGMT (53, 47.3%). In normal mucosa, hMSH2 (6, 5.4%) and MGMT (12, 10.7%) were methylated, whereas hMLH1 was not. Immunohistochemical analysis revealed abnormal hMLH1 (14, 12.5%), hMSH2 (11, 9.8%), and MGMT (53, 47.3%) expression with a significant correlation between aberrant MGMT methylation and a loss of MGMT expression.

Conclusions

These data suggest that CpG island methylation in hMSH2 and MGMT, but not hMLH1, is closely related to carcinogenesis in colorectal carcinomas presenting with a conventional adenoma–carcinoma sequence. Therefore, the detection of hMSH2 and MGMT methylation may have clinical significance in the evaluation of colon cancer patients and in tumor-specific management of the disease.

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Acknowledgment

This study was sponsored by grants from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (0720570) and the Brain Korea 21 Project, Center for Biomedical Human Resources at Chonnam National University.

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Authors and Affiliations

  1. Department of Pathology, Chonnam National University Medical School, 8, Hak-dong, Dong-gu, Gwangju, 501-757, South Korea

    Kyung-Hwa Lee, Ji-Shin Lee, Jong-Hee Nam, Chan Choi, Min-Cheol Lee, Chang-Soo Park, Sang-Woo Juhng & Jae-Hyuk Lee

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The work presented here was carried out in collaboration between all authors. All authors have contributed to, seen, and approved the manuscript.

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Lee, KH., Lee, JS., Nam, JH. et al. Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma–carcinoma sequence. Langenbecks Arch Surg 396, 1017–1026 (2011). https://doi.org/10.1007/s00423-011-0812-9

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