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

(1) Background: 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, 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, 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 protein expression and microsatellite instability. All cases were investigated for promoter methylation and germline variants. (3) Results: Somatic promoter hypermethylation was identified in 16.7% of CRC and in 40% of EC carriers of germline pathogenic variants. In two families, primary and secondary epimutations were demonstrated. (4) Conclusions: hypermethylation should not be exclusively considered as a sporadic cancer mechanism, as a non-negligible number of LS-related cancers are hypermethylated. Current flow charts for universal LS screening, which include methylation, should be applied, paying attention to a patient's family and personal history.