hMLH1 Promoter Hypermethylation Is an Early Event in Human Endometrial Tumorigenesis
It has recently been suggested that silencing of the hMLH1 gene by promoter hypermethylation is the mechanism underlying the presence of the microsatellite instability (MSI. phenotype in sporadic colon and endometrial carcinomas. To determine whether hMLH1 promoter hypermethylation is a relatively e...
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Veröffentlicht in: | The American journal of pathology 1999-11, Vol.155 (5), p.1767-1772 |
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Sprache: | eng |
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Zusammenfassung: | It has recently been suggested that silencing of the
hMLH1 gene by promoter hypermethylation is the mechanism underlying the presence of the microsatellite instability (MSI. phenotype in sporadic colon and endometrial carcinomas. To determine whether
hMLH1 promoter hypermethylation is a relatively early event in endometrial tumorigenesis we evaluated endometrial hyperplasia (EH) characterized as simple, complex, and atypical (the direct precursor of endometrial carcinoma) for
hMLH1 aberrant methylation. In addition, we studied the
hMLH1, hMSH2, hMSH3, and
hMSH6 promoter methylation and MSI status of those endometrial carcinomas with synchronous hyperplasias and those without them. We found that 11 of 12 (91%) cases of endometrial carcinoma (EC. displaying MSI had
hMLH1 promoter hypermethylation, whereas aberrant methylation of any of the other mismatch repair genes was not observed. All 15 cases of EC without MSI were unmethylated at
hMLH1. Abnormal methylation of
hMLH1 was also present in 8 of 116 (7%. cases of EH and was restricted primarily to the atypical endometrial hyperplasia (AEH) type with coexisting endometrial carcinoma. In this set, half of EH methylated at
hMLH1 displayed MSI, whereas none of the unmethylated EH had MSI. Our data suggest that hypermethylation of
hMLH1 can be an early event in the pathogenesis of EC, preceding the development of an apparent MSI phenotype in a subset of cases. |
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ISSN: | 0002-9440 1525-2191 |
DOI: | 10.1016/S0002-9440(10)65492-2 |