Constitutional (germline) MLH1 epimutation as an aetiological mechanism for hereditary non-polyposis colorectal cancer

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome characterised by a predisposition to early onset colorectal, endometrial and other cancers. The tumours typically exhibit microsatellite instability due to defective mismatch repair. HNPCC is classically caused by heterozygous loss-of-function mutations within the mismatch repair genes MLH1, MSH2, MSH6 and PMS2, but no pathogenic mutations are identified in a third of cases. In recent years, constitutional epimutations of the MLH1 gene, characterised by soma-wide allele specific promoter methylation and transcriptional silencing, have been identified in a handful of mutation negative HNPCC cases. In contrast to genetic mutations, MLH1 epimutations are reversible between generations and thus display non-Mendelian inheritance. This review focuses on the aetiological role of constitutional MLH1 epimutations in the development of HNPCC related cancers. The molecular characteristics, clinical ramifications and potential mechanism underlying this defect are discussed. Recommendations for the selection of cases warranting screening for MLH1 epimutations are proffered.