Promoter Hypermethylation and Lynch Syndrome: When to Test for Constitutional Epimutations of Gene?

Lynch syndrome is a genetic condition predisposing to cancer, particularly colorectal cancer and endometrial cancer, due to germline mutations in MisMatch Repair genes. More rarely, Lynch syndrome is the result of a constitutional promoter methylation. This review summarizes the current knowledge about the role of this epigenetic mechanism in the Lynch syndrome. Universal Tumor Screening, performed on tumoral specimens to identify features suggestive of Lynch syndrome, shows the same features both in the case of sporadic cancers and Lynch syndrome-cancers due to a constitutional methylation: microsatellite instability, deficiency of MisMatch Repair proteins, and methylation of gene. Over the last few years, identifying methylation of promoter on tumors was used to discern sporadic tumors from Lynch syndrome tumors: the methylation of the promoter was usually explained as a somatic event and this could lead to a missed diagnosis of some Lynch syndrome cases. Therefore, establishing criteria to decide when to test patients for constitutional methylation is urgent. In the case of microsatellite instability/deficiency of MisMatch Repair tumors with methylation, a germline genetic test could be requested for all colorectal cancer patients aged 55 years or younger and all endometrial cancer patients younger than 50 years old, independently from family history. The prevalence of germline epimutations is not precisely known and possibly underestimated. The associated cancer risk could be similar to that due to a sequence variant. epimutations could be secondary to other genetic defects and follow an autosomal dominant inheritance. On the contrary, primary epimutations are often "" events, and their transmission does not follow Mendelian rules.