Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers

Abstract

Endometrial cancer is the most common gynecologic malignancy in the United States and the most frequent extracolonic tumor in hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC patients have inherited defects in DNA mismatch repair and the microsatellite instability (MSI) tumor phenotype. Sporadic endometrial cancers also exhibit MSI, usually associated with methylation of the MLH1 promoter. Germ-line MSH6 mutations, which are rare in HNPCC, have been reported in several families with multiple members affected with endometrial carcinoma. We reasoned that MSH6 mutation might account for loss of mismatch repair in MSI-positive endometrial cancers in which the cause of MSI is unknown. We therefore investigated MSI and MLH1 promoter methylation in 441 endometrial cancer patients unselected for age or personal and family history of cancers. MSI and MLH1 promoter methylation status were associated with age of onset and tumor histology. One hundred cases (23% of the entire series) were evaluated for MSH6 defects. Inactivating germ-line MSH6 mutations were identified in seven women with MSI-positive, MLH1 promoter unmethylated cancers. Most of the MSI in these cases was seen with mononucleotide repeat markers. The MSH6 mutation carriers were significantly younger than the rest of the population (mean age 54.8 versus 64.6, P ‫؍‬ 0.04). Somatic mutations were seen in 17 tumors, all of which had MSI. Our data suggest that inherited defects in MSH6 in women with endometrial cancer are relatively common. The minimum estimate of the prevalence of inherited MSH6 mutation in endometrial cancer is 1.6% (7 of 441), comparable with the predicted prevalence for patients with colorectal cancer.T he link between defective DNA mismatch repair and the development of tumors has been firmly established. Inherited mutations in DNA mismatch repair genes are associated with the autosomal dominant cancer susceptibility syndrome, hereditary nonpolyposis colorectal cancer (HNPCC). Patients with HNPCC are at high risk for colorectal and endometrial cancer and a variety of other malignancies. Tumors from HNPCC patients frequently show mutations in repetitive sequences, giving rise to a molecular phenotype referred to as microsatellite instability (MSI). Not surprisingly, a significant fraction of sporadic colorectal and endometrial cancers also show MSI.Most families with clinically recognized HNPCC have mutations in either MLH1 or MSH2. MSH6 mutations appear to be associated with atypical HNPCC and in particular with development of endometrial carcinoma or atypical endometrial hyperplasia, the presumed precursor of endometrial cancer (1-4). The age of onset of cancers in HNPCC kindreds with MSH6 mutations is higher than in MSH2 or MLH1 mutation carriers, and it has been reported that tumors from affected family members are less likely to have high MSI than tumors from MSH2 or MLH1 mutation carriers (5).The estimated frequency of MSH6 mutation in patients with colorectal cancer ranges between 0% based on a tumor immunohistochemistry study ...

MLH1 Polymorphisms and Cancer risk: a Meta-analysis Based on 33 Case-control Studies

“…Further and larger samples study need to identify the association and the role of polymorphism I219V in carcinogenesis. Epigenetic silencing of the MLH1 gene is one of the most common causes of DNA mismatch repair capacity deficiency (Goodfellow et al, 2003). Some study has indicated that the SNP -93G>A may increase the susceptibility of the promoter sequence to methylation.…”

“…Because this polymorphism is located in a CpG island (which occurs at the cytosines of the CpG dinucleotides, and often occurs in clusters), adjacent to CpG cites that are able to undergo methylation (Deng et al, 2001). Goodfellow et al (2003) reported >20% MLH1 gene promoter methylation occurred in a large series of endometrial carcinomas. Chen et al (2007) have showed the variant alleles of SNP -93G>A on MLH1 was associated with MLH1 gene methylation in endometrial and colorectal cancers.…”

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.…”

“…16 MSI is a molecular feature of approximately one quarter of sporadic human endometrial carcinomas. 5,17,18 Given the histologic and molecular similarities between human endometrial cancers and the lesions that arise in DES-treated mice, we reasoned that the DES murine model was an appropriate experimental system in which to begin to identify genes and genetic networks that are disrupted in estrogen-driven endometrial tumorigenesis. We conducted these studies on genetically homogenous inbred animals, and controlled exposure to the synthetic estrogen in an effort to provide a hormonally homogenous environment in which tumors develop.…”

Functional effects of the MLH1-93G>A polymorphism on MLH1/EPM2AIP1 promoter activity

“…Furthermore, the majority of MSI-H CRCs occur due to the epigenetic silencing of the MLH1 promoter (4). MMR deficiency has also been shown to give rise to sporadic endometrial cancer with 28% of all endometrial tumours displaying a loss of MMR (5). Moreover, endometrial cancer is also the most common extra-colonic malignancy observed in the Lynch syndrome (6).…”