J Med Genet 46:793-802 doi:10.1136/jmg.2009.068122
  • Review

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

  1. M P Hitchins,
  2. R L Ward
  1. Integrated Cancer Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, Australia
  1. Correspondence to Dr M P Hitchins, UNSW Cancer Research Centre University of New South Wales Randwick Sydney, Australia, NSW 2052; m.hitchins{at}
  • Received 24 March 2009
  • Revised 25 May 2009
  • Accepted 10 June 2009
  • Published Online First 29 June 2009


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.


  • Funding MPH is supported by a Career Development and Support Fellowship from the Cancer Institute NSW and research funds from the Australian NH&MRC.

  • Competing interests None.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.