The role of epigenetics in Lynch syndrome

Recognition by Warthin of the familial clustering of colorectal and gynaecological cancers a century ago laid the foundation for the recognition of familial cancer. By tracking afflicted pedigrees, Lynch defined the clinical characteristics and argued for a heritable genetic component to this autosomal dominant cancer susceptibility condition, now termed Lynch syndrome. This was proven in the 1990s, with the discovery of deleterious germline mutations of the mismatch repair genes as its cause. Yet despite the genetic revolution at the turn of the twenty-first century, no pathogenic mutation was identifiable in approximately one-third of cases with suspected Lynch syndrome. In the past decade, the alternative mechanism of constitutional epimutation of the two major mismatch repair genes, MLH1 and MSH2, was identified in a proportion of these outstanding cases. This epigenetic defect, characterized by methylation and transcriptional inactivation of a single genetic allele within normal tissues, predisposes to the development of Lynch-type cancers. MSH2 and some MLH1 epimutations have been linked to genetic alterations within their vicinity and demonstrate dominant inheritance, whilst other MLH1 epimutations are reversible between generations and demonstrate non-Mendelian inheritance. This review charts the discovery of mismatch repair epimutations, their aetiological role in Lynch syndrome and the mechanistic basis for their variable inheritance patterns.