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Expression and promoter methylation status of mismatch repair gene hMLH1 and hMSH2 in epithelial ovarian cancer
Author(s) -
ZHANG Hui,
ZHANG Shiqian,
CUI Jing,
ZHANG Aifeng,
SHEN Liang,
YU Hao
Publication year - 2008
Publication title -
australian and new zealand journal of obstetrics and gynaecology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.734
H-Index - 65
eISSN - 1479-828X
pISSN - 0004-8666
DOI - 10.1111/j.1479-828x.2008.00892.x
Subject(s) - methylation , ovarian cancer , dna methylation , cancer research , demethylating agent , dna mismatch repair , metastasis , medicine , microbiology and biotechnology , cancer , biology , gene , gene expression , colorectal cancer , genetics
Objective: The purpose of this study is to determine the relationship between methylation and loss of hMLH1 and hMSH2 expression in ovarian cancer. Methods: We examined the methylation status of hMLH1 and hMSH2 promoter region by methylation‐specific polymerase chain reaction (MSP) in 56 primary ovarian cancer tissues and 20 normal ovarian tissues, the relationship between the methylation status of these two genes and clinicopathological characteristics were analysed. We then treated SKOV3 and 3AO ovarian cancer cell lines with the demethylating agent 5‐aza‐2′‐deoxycytidine (5‐aza‐dc). The hMLH1 and hMSH2 methylation was further assessed by MSP, and their mRNA expression was compared by reverse transcription polymerase chain reaction (RT‐PCR) before and after 5‐aza‐dc treatment in these two cell lines. Results: The methylation frequency of hMLH1 and hMSH2 was 30.4% (17 of 56) and 51.7% (29 of 56) in ovarian cancers, respectively, while no methylation was detected in normal ovarian tissues ( P = 0.015). There is a significant correlation between hMLH1 promoter hypermethylation and histological grade ( P = 0.028) as well as lymphatic metastasis ( P = 0.003). Methylation of hMSH2 correlated with histological grade ( P = 0.035) and lymphatic metastasis ( P = 0.015). Besides, the methylation rates of hMSH2 were significantly higher in endometrioid adenocarcinoma tissues than in other pathological types of ovarian cancer. After 5‐aza‐dc treatment, the expression of hMLH1 and hMSH2 was reversed in two cell lines. Conclusion: Our results indicate that promoter hypermethylation is an important mechanism for loss of hMLH1 and hMSH2 expression in human ovarian cancer and may be a potential prognostic factor in ovarian cancer.