The "unnatural" history of colorectal cancer in Lynch syndrome: Lessons from colonoscopy surveillance

Int J Cancer. 2021 Feb 15;148(4):800-811. doi: 10.1002/ijc.33224. Epub 2020 Aug 3.


Individuals with Lynch syndrome (LS), one of the most common inherited cancer syndromes, are at increased risk of developing malignancies, in particular colorectal cancer (CRC). Regular colonoscopy with polypectomy is recommended to reduce CRC risk in LS individuals. However, recent independent studies demonstrated that a substantial proportion of LS individuals develop CRC despite regular colonoscopy. The reasons for this surprising observation confirmed by large prospective studies are a matter of debate. In this review, we collect existing evidence from clinical, epidemiological and molecular studies and interpret them with regard to the origins and progression of LS-associated CRC. Alongside with hypotheses addressing colonoscopy quality and pace of progression from adenoma to cancer, we discuss the role of alternative precursors and immune system in LS-associated CRC. We also identify gaps in current knowledge and make suggestions for future studies aiming at improved CRC prevention for LS individuals.

Keywords: Lynch syndrome; colonoscopy surveillance; colorectal cancer; incident cancer risk; microsatellite instability; mismatch repair deficiency.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Colonoscopy / methods*
  • Colorectal Neoplasms / diagnosis*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms, Hereditary Nonpolyposis / diagnosis*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics
  • DNA Mismatch Repair / genetics
  • DNA Repair Enzymes / genetics
  • Humans
  • Mass Screening / methods
  • Microsatellite Instability
  • Population Surveillance / methods*
  • Risk Factors


  • DNA Repair Enzymes