Abstract
Germline mutation of DNA mismatch repair (MMR) genes is a cause of Lynch syndrome. Methylation of MutL homolog 1 (MLH1) and MutS homolog 2 (MSH2) has been detected in peripheral blood cells of patients with colorectal cancer. This methylation is referred to as epimutation. Methylation of these genes has not been studied in an unselected series of endometrial cancer cases. Therefore, we examined methylation of MLH1, MSH2, and MSH6 promoter regions of peripheral blood cells in 206 patients with endometrial cancer using a methylation-specific polymerase chain reaction (MSP). Germline mutation of MMR genes, microsatellite instability (MSI), and immunohistochemistry (IHC) were also analyzed in each case with epimutation. MLH1 epimutation was detected in a single patient out of a total of 206 (0.49%)—1 out of 58 (1.72%) with an onset age of less than 50 years. The patient with MLH1 epimutation showed high level MSI (MSI-H), loss of MLH1 expression and had developed endometrial cancer at 46 years old, complicated with colorectal cancer. No case had epimutation of MSH2 or MSH6. The MLH1 epimutation detected in a patient with endometrial cancer may be a cause of endometrial carcinogenesis. This result indicates that it is important to check epimutation in patients with endometrial cancer without a germline mutation of MMR genes.
Highlights
Lynch syndrome is an autosomal dominant syndrome characterized by early development of colorectal and endometrial cancers, with an elevated risk of ovarian and other cancers [1]
We could not definitively rule out the possibility of familial adenomatous polyposis (FAP) because the medical records of her colorectal cancer and her relatives’ cancers were unavailable to us, since they were treated at other hospitals
Germline genetic testing showed no mutation of mismatch repair (MMR) genes (MLH1, MutS homolog 2 (MSH2), and MSH6)
Summary
Lynch syndrome is an autosomal dominant syndrome characterized by early development of colorectal and endometrial cancers, with an elevated risk of ovarian and other cancers [1]. Lynch syndrome accounts for 2%–6% of cases of endometrial cancer and is caused by germline mutations in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) [2]. Genomic rearrangements in the epithelial cell adhesion molecule (EPCAM) gene can lead to a silencing of the closely linked. These genes encode components of the mismatch repair system, which comprises two main protein complexes: the MutL homologue (MLH1, PMS2) and the MutS homologue (MSH2, MSH6). An aberration in one of these genes, and loss of these proteins, prevent appropriate repair of base mismatches produced during DNA replication.
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