Molecular pathology of Lynch syndrome

J Pathol. 2020 Apr;250(5):518-531. doi: 10.1002/path.5422.


Lynch syndrome (LS) is characterised by predisposition to colorectal, endometrial, and other cancers and is caused by inherited pathogenic variants affecting the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. It is probably the most common predisposition to cancer, having an estimated prevalence of between 1/100 and 1/180. Resources such as the International Society for Gastrointestinal Hereditary Cancer's MMR gene variant database, the Prospective Lynch Syndrome Database (PLSD), and the Colon Cancer Family Register (CCFR), as well as pathological and immunological studies, are enabling advances in the understanding of LS. These include defined criteria by which to interpret gene variants, the function of MMR in the normal control of apoptosis, definition of the risks of the various cancers, and the mechanisms and pathways by which the colorectal and endometrial tumours develop, including the critical role of the immune system. Colorectal cancers in LS can develop along three pathways, including flat intramucosal lesions, which depend on the underlying affected MMR gene. This gives insights into the limitations of colonoscopic surveillance and highlights the need for other forms of anti-cancer prophylaxis in LS. Finally, it shows that the processes of autoimmunisation and immunoediting fundamentally constrain the development of tumours in LS and explain the efficacy of immune checkpoint blockade therapy in MMR-deficient tumours. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: DNA mismatch repair; Lynch syndrome; apoptosis; colorectal cancer; endometrial cancer; gene database; gene variant interpretation; immunoediting; immunotherapy.

Publication types

  • Review

MeSH terms

  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / pathology
  • DNA Mismatch Repair / genetics
  • DNA-Binding Proteins / genetics
  • Endometrial Neoplasms / genetics
  • Endometrial Neoplasms / pathology*
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Pathology, Molecular* / methods


  • DNA-Binding Proteins