Mutations predisposing to hereditary nonpolyposis colorectal cancer

Adv Cancer Res. 1997;71:93-119. doi: 10.1016/s0065-230x(08)60097-4.


Since 1993 four genes have been identified that, when mutated, confer predisposition to a form of hereditary colon cancer (hereditary nonpolyposis colorectal cancer [HNPCC]). These genes belong to the Mut-related family of DNA mismatch repair genes whose protein products are responsible for the recognition and correction of errors that arise during DNA replication. Mutational inactivation of both copies of a DNA mismatch repair gene results in a profound repair defect demonstrable by biochemical assays, and in vivo this defect is presumed to lead to progressive accumulation of secondary mutations throughout the genome, some of which affect important growth-regulatory genes and, hence, give rise to cancer. To date, more than 70 different germline mutations have been detected in DNA mismatch repair genes and shown to be associated with HNPCC. Current evidence suggests that two genes, MSH2 and MLH1, account for roughly equal proportions of HNPCC kindreds, together being responsible for a majority of these families, but striking interethnic differences occur. Most mutations lead to truncated protein products. Mutation screening is quite demanding in HNPCC since, with a few exceptions, the predisposing mutations typically vary from kindred to kindred and individual mutations are scattered throughout the genes. Knowledge of the predisposing mutations allows genotype-phenotype correlations and forms the basis for further studies clarifying the pathogenesis of this disorder. In at-risk individuals, it allows predictive testing for cancer susceptibility and, consequently, appropriate clinical management of mutation carriers and noncarriers.

Publication types

  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adenoma / complications
  • Adenosine Triphosphatases*
  • Carrier Proteins*
  • Chromosomes, Human, Pair 2
  • Colonic Neoplasms / genetics
  • Colorectal Neoplasms / complications
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • DNA Repair
  • DNA Repair Enzymes*
  • DNA-Binding Proteins*
  • Fungal Proteins / genetics
  • Humans
  • Microsatellite Repeats / genetics
  • Mismatch Repair Endonuclease PMS2
  • MutL Protein Homolog 1
  • MutL Proteins
  • MutS Homolog 2 Protein
  • Mutation
  • Neoplasm Proteins / genetics
  • Nuclear Proteins
  • Phenotype
  • Proteins / genetics
  • Proto-Oncogene Proteins / genetics


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA-Binding Proteins
  • Fungal Proteins
  • MLH1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • PMS1 protein, human
  • Proteins
  • Proto-Oncogene Proteins
  • Adenosine Triphosphatases
  • PMS2 protein, human
  • MSH2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • MutL Protein Homolog 1
  • MutL Proteins
  • MutS Homolog 2 Protein
  • DNA Repair Enzymes