MLH1 Promoter Methylation and Gene Silencing is the Primary Cause of Microsatellite Instability in Sporadic Endometrial Cancers

Abstract

Defective DNA mismatch repair in human tumors leads to genome-wide instability of microsatellite repeats and a molecular phenotype referred to as microsatellite instability (MSI). MSI has been reported in a variety of cancers and is a consistent feature of tumors from patients with hereditary non-polyposis colorectal cancer. Approximately 20% of cancers of the uterine endometrium, the fifth most common cancer of women world-wide, exhibit MSI. Although the frequency of MSI is higher in endometrial cancers than in any other common malignancy, the genetic basis of MSI in these tumors has remained elusive. We investigated the role that methylation of the MLH1 DNA mismatch repair gene plays in the genesis of MSI in a large series of sporadic endometrial cancers. The MLH1 promoter was methylated in 41 of 53 (77%) MSI-positive cancers investigated. In MSI-negative tumors on the other hand, there was evidence for limited methylation in only one of 11 tumors studied. Immunohistochemical investigation of a subset of the tumors revealed that methylation of the MLH1 promoter in MSI-positive tumors was associated with loss of MLH1 expression. Immunohistochemistry proved that two MSI-positive tumors lacking MLH1 methylation failed to express the MSH2 mismatch repair gene. Both of these cancers came from women who had family and medical histories suggestive of inherited cancer susceptibility. These observations suggest that epigenetic changes in the MLH1 locus account for MSI in most cases of sporadic endometrial cancers and provide additional evidence that the MSH2 gene may contribute substantially to inherited forms of endometrial cancer.

DNA Repair and Tumorigenesis: Lessons from Hereditary Cancer Syndromes

“…However, 15-40% of sporadic colorectal, endometrial, ovarian and upper urinary tract tumors also display MSI. [11][12][13][14] This observation requires inactivation of two wild type MMR alleles early in the tumorigenesis process. While the majority of these sporadic cases inactivated the expression of hMLH1 by hypermethylation of the promoter region, 15 some 10-20% contain mutational inactivation of two alleles.…”

Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach

“…In occasional EC tumors studied from HNPCC patients, LOH (for MSH2 and MSH6; Ollikainen et al, 2005) and somatic frameshift mutations (for MSH6; Wijnen et al, 1999) have been implicated. Sporadic EC resembles sporadic CRC, in that MLH1 promoter methylation appears to be the primary mechanism of MSI (Esteller et al, 1998;Simpkins et al, 1999). In general, somatic point mutations rarely explain MMR gene inactivation in CRC (Tannergard et al, 1997;Kuismanen et al, 2000;Potocnik et al, 2001;Yuen et al, 2002) or EC (Chadwick et al, 2001).…”

Transcriptional profiling endometrial carcinomas microdissected from DES‐treated mice identifies changes in gene expression associated with estrogenic tumor promotion

“…Molecular and epidemiological studies have highlighted key genetic factors in human endometrial tumorigenesis, including loss or epigenetic silencing of the tumor suppressor gene phosphatase and tensin homologue (PTEN) 1 and the DNA mismatch repair (MMR) genes mutL homologue 1 (MLH1), mutS homologue 2 (MSH2) and mutS homologue 6 (MSH6). [2][3][4][5] It is widely accepted that exposure to unopposed estrogen (estrogen in the absence of progesterone) is a potent environmental risk factor for the development of a variety of malignancies, and in particular endometrial carcinoma. [6][7][8] However, deciphering the genes and pathways that are disturbed in estrogen-promoted endometrial cancers has been a difficult task, due in part to the inherent genetic and hormonal heterogeneity that characterizes this tumor type.…”