Constitutional methylation of the MLH1 gene is a rare and often overlooked cause of Lynch Syndrome. The current screening strategies to detect Lynch Syndrome often are truncated when a tumor is found to be methylated, assuming such silencing is somatic. Typically, only when additional clues occur in the proband with a methylated MLH1 promotor finding in a colorectal cancer, such as multiple Lynch-associated tumors occurring synchronously or metachronously, is constitutional methylation contemplated. This scientific field is looking for a more systematic analysis of this possibility, and a deeper understanding of the possible inheritance patterns of probands with constitutional methylation, and any DNA variation that might predispose to the phenomenon (including cryptic DNA variations not typically found on diagnostic multigene panel tests, such as non-coding promoters, intronic, or structural variation). Furthermore, extension of the concept to other mismatch repair genes, other cancer predisposing genes (e.g., BRCA) could prove informative.

The challenges are to gain broader acceptance of the possibility of constitutional methylation in clinic practice and research, especially from a systematic perspective, and to introduce technologies that sequence more deeply into the non-coding environment of genes susceptible to the phenomenon.

The aim of this Special Issue is to identify the experience of constitutional methylation in MLH1, MMR, or cancer-related genes, allowing insights into the frequency and mechanisms that underpin this process. We welcome original research and review articles.

Potential topics include but are not limited to the following:

• Systematic genetic epidemiological studies to identify the prevalence of constitutional MLH1 methylation in patients with colorectal, endometrial, and other cancers
• Systematic documentation of pathological, genomic, and epigenomic features of tumors from patients with constitutional MLH1 methylation
• Description of cancer phenotypes in carriers of constitutional MLH1 methylation, of both primary (with no apparent genetic basis) and secondary (linked to a causal genetic variant) types
• Systematic search for genetic drivers of constitutional MLH1 methylation
• Study of inheritance patterns in patients with constitutional MLH1 methylation
• Systematic genetic epidemiological studies to identify the prevalence of constitutional BRCA1 or 2 methylation in patients with breast, ovarian, and other cancers
• Systematic documentation of pathological, genomic, and epigenomic features of tumors from patients with constitutional BRCA1 or 2 methylation
• Description of cancer phenotypes in carriers of constitutional BRCA1 or 2 methylation (of both primary and secondary types)
• Systematic search for genetic drivers of constitutional BRCA 1 or 2 methylation
• Studies of inheritance patterns in patients with constitutional BRCA1 or 2 methylation
• Description of constitutional methylation of any other cancer-related gene
• Description of genetic variants associated with the development of somatic aberrant methylation in cancer (e.g., MLH1, MGMT, BRCA)