hMLH1 Promoter Hypermethylation Is an Early Event in Human Endometrial Tumorigenesis

Abstract

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. (Am J Pathol 1999, 155:1767-1772)Endometrial carcinoma is the most common gynecological malignancy and is the fourth most common cancer of women in the United States.1 Uterine endometrioid carcinoma (UEC) is the most common histological type. UEC often precedes or coexists with endometrial hyperplasias, which have been proposed as possible precursor lesions.2,3 Atypical endometrial hyperplasia (AEH) is most associated with progression to carcinoma, and women with AEH without concurrent invasive carcinoma have a 30% risk of developing UEC.3 UEC and AEH share cytological atypia and a monoclonal pattern, 4,5 but UEC are distinguished by the presence of invasion.3 A spectrum of hyperplasia without atypia, including simple and complex hyperplasia, also exists. These lesions show a low rate of progression to UEC 3 and a putative polyclonal pattern. 4,5Very little is known about the genetic alterations underlying the biology of the precursor lesions of UEC. Only mutations in the oncogene K-ras and the tumor suppressor gene PTEN have been described in AEH.6,7 PTEN mutations may even precede the appearance of an evident atypia in the endometrial hyperplasia.8 However, a subset of AEH displays the microsatellite instability (MSI) phenotype.5,7,9,10 MSI was first detected in tumors from patients with hereditary non-polyposis colorectal carcinoma (HNPCC). In this setting, the cause of MSI has been attributed to germline defects in DNA mismatch repair (MMR) genes, mainly involving hMLH1 and hMSH2. 11-19Other MMR genes identified include hPMS1, hPMS2, hMSH3, and hMSH6. 20 -21 Endometrial carcinoma (EC) is the most com...

Urokinase plasminogen activator receptor: Prognostic biomarker for endometrial cancer

“…These criteria are rarely satisfied because most candidate prognostic markers fail to distinguish between tumors that require adjuvant treatment and those that do not. For example, tumor suppressor gene(s) (e.g., p53), oncogene(s) (e.g., HER2͞neu, K-ras), and DNA repair gene(s) (e.g., hMLH1), microsatellite instability, and͞or protein-tyrosine phosphatase (PTEN) mutation and͞or ras mutation have played a role in endometrial cancer (2)(3)(4)(5)(6)(7)(8)(9). However, none of these genes have proven to be clinically useful prognostic markers for endometrial cancer.…”

Histone deacetylase inhibitors induce apoptosis in both Type I and Type II endometrial cancer cells

“…In endometrial cancer, DNA hypermethylation and/or histone deacetylation mechanisms are directly involved in the silencing of hMLH1/MSH2, PTEN, and progesterone receptor (PR). hMLH1/MSH2 has been observed in atypical hyperplasia, a finding suggesting that epigenetic alterations may be an early event in carcinogenesis [12,13]. PTEN expression is associated with more aggressive tumors and poor outcomes [14].…”

hMLH1 and MGMT inactivation as a mechanism of tumorigenesis in monoclonal gammopathies

“…12 Methylation changes are often detected in premalignant or precursor lesions, (before malignant changes) and, thus, may be of use in early detection of cancer. 13 During replication, the primary function of the eukaryotic DNA mismatch repair (MMR) system is to recognise and correct mismatched base pairs within the DNA helix. The DNA MMR system is expressed in all tissues at various levels and plays an important role in the maintenance of genomic integrity.…”