MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis

Abstract

(1) Background: MLH1 hypermethylation is an epigenetic alteration in the tumorigenesis of colorectal cancer (CRC) and endometrial cancer (EC), causing gene silencing, and, as a consequence, microsatellite instability. Commonly, MLH1 hypermethylation is considered a somatic and sporadic event in cancer, and its detection is recognized as a useful tool to distinguish sporadic from inherited conditions (such as, Lynch syndrome (LS)). However, MLH1 hypermethylation has been described in rare cases of CRC and EC in LS patients. (2) Methods: A total of 61 cancers (31 CRCs, 27 ECs, 2 ovarian cancers, and 1 stomach cancer) from 56 patients referred to cancer genetic counselling were selected for loss of MLH1 protein expression and microsatellite instability. All cases were investigated for MLH1 promoter methylation and MLH1/PMS2 germline variants. (3) Results: Somatic MLH1 promoter hypermethylation was identified in 16.7% of CRC and in 40% of EC carriers of MLH1 germline pathogenic variants. In two families, primary and secondary MLH1 epimutations were demonstrated. (4) Conclusions: MLH1 hypermethylation should not be exclusively considered as a sporadic cancer mechanism, as a non-negligible number of LS-related cancers are MLH1 hypermethylated. Current flow charts for universal LS screening, which include MLH1 methylation, should be applied, paying attention to a patient’s family and personal history.

A tale of two pathways: Review of immune checkpoint inhibitors in DNA mismatch repair‐deficient and microsatellite instability‐high endometrial cancers

“…41,42 However, there have been rare reports of MLH1 promoter hypermethylation in those with MLH1-associated LS, where the methylation serves as a "second hit" in tumor development. 43 Constitutional methylation of MLH1 is also a rare but important mechanism of LS to recognize. 44 Therefore, assessments of family history and additional genetic testing remain important.…”

“…This involves assessment of DNA hypermethylation at the CpG islands in the promoter region 41,42 . However, there have been rare reports of MLH1 promoter hypermethylation in those with MLH1 ‐associated LS, where the methylation serves as a “second hit” in tumor development 43 . Constitutional methylation of MLH1 is also a rare but important mechanism of LS to recognize 44 .…”

Real-World Data on Institutional Implementation of Screening for Mismatch Repair Deficiency and Lynch Syndrome in Endometrial Cancer Patients

“…An additional issue to be discussed for future directions in clinical screening for Lynch syndrome is the possibility of MLH1 hypermethylation in Lynch syndrome patients who are carriers of a pathogenic MLH1 germline variant [36][37][38] or who are carriers of a constitutional, possibly hereditary, MLH1 epimutation [36,[39][40][41]. The co-occurrence of a somatic MLH1 hypermethylation with a germline MLH1 mutation has been described in a proportion of more than 15%, indicating that Lynch syndrome cannot be excluded when MLH1 promoter hypermethylation is observed [36].…”

High Probability of Lynch Syndrome among colorectal cancer patients in Indonesia is associated with higher occurrence of KRAS and PIK3CA mutations

“…Testing for MSI and MMR protein deficiency is commonly the first step in LS diagnostics due to germline mutations of MMR genes. On the contrary, epigenetic silencing of the MLH1 and somatic mutation of BRAF are common in sporadic tumors with MSI but very rarely occur in tumors arising in LS [13,14]. KRAS mutations, the most common RAS family mutation, affect cell proliferation, differentiation, senescence, and apoptosis in 40% of sporadic CRC.…”

“…Testing for MSI and MMR protein deficiency is commonly the first step in LS diagnostics due to germline mutations of MMR genes. On the contrary, epigenetic silencing of the MLH1 and somatic mutation of BRAF are common in sporadic tumors with MSI but very rarely occur in tumors arising in LS [13, 14].…”