{13, 1686, 1451, 1349}

However, microsatellite instability is not specific to HNPCC, occurring in 10 to 15% of apparently sporadic colorectal and other tumours as well {164}. Correction of biosynthetic errors in the newly synthesized DNA is not the only function of the DNA mismatch repair system. In particular, it is also able to recognize lesions caused by exogenous mutagens, and has been shown to participate in transcription-coupled repair {134, 1215}.

Gene mutations

The International Collaborative Group on HNPCC maintains a database for HNPCC-associated mutations and polymorphisms ( The great majority is found in MLH1 and MSH2, with a few mutations in MSH6, PMS1 and PMS2. These mutations occur in over 400 HNPCC families from different parts of the world {485}. Most MSH2 and MLH1 mutations are truncating {1488}. However, one-third of MLH1 mutations is of missense type, which constitutes a diagnostic problem concerning their pathogenicity. Commonly used theoretical criteria in support of pathogenicity include the following: the mutation leads to a nonconservative amino acid change, the involved codon is evolutionarily conserved, the change is absent in the normal population, and it segregates with the disease phenotype. A subset of such mutations was directly assessed for pathogenicity using a yeast-based functional assay, and there was a good correlation {1745}. As a rule, the mutations are scattered throughout the genes, but exon 12 in MSH2 and exon 16 in MLH1 constitute particular hot spots {1488}.

Mutations in the five DNA mismatch repair genes account for two-thirds of all classical HNPCC families meeting the Amsterdam criteria and showing MSI in tumours {1078}. Occurrence of these mutations is clearly lower (< 30%) in HNPCC kindreds not meeting the Amsterdam criteria {1379, 2103}. Moreover, clinically indistinguishable phenotype (non-polypotic colon cancer plus variable extracolonic cancers) may be associated with germline mutations in genes that are not involved in DNA mismatch repair, such as TGFp-RII {1103} and E-Cadherin {1581}. As expected, tumours from such families do not characteristically show MSI.

Prognosis and predictive factors

HNPCC mutations generally have a high penetrance. There is no clear-cut correlation between the involved gene, mutation site within the gene, or mutation type vs. clinical features. MSH2 mutations may confer higher risk for extracolonic cancer as compared to MLH1 mutations {2005}. MSH6mutations may be associated with atypical clinical features, including common occurence of endometrial cancer {2102} and late age of onset {29}. Finally, capability of the mutant protein to block the normal homologue by a dominant negative fashion may lead to a severe phenotype, in which even normal cells may manifest mismatch repair deficiency {1475, 1348}. Conversely, inability to do so may be associated with a milder phenotype and lack of extracolonic cancers {828}. Kindreds with the Muir-Torre phenotype {971} as well as a subset of those with Turcot syndrome {658} show mutations similar to those observed in classical HNPCC.

Juvenile polyposis


Juvenile polyposis (JP) is a familial cancer syndrome with autosomal dominant trait, characterized by multiple juvenile polyps of the gastrointestinal tract, involving predominantly the colorectum, but also the stomach and the small intestine. In addition to colorectal cancer, JP patients carry an increased risk for the development of tumours in the stomach, duodenum, biliary tree and pancreas.



Was this article helpful?

0 0
10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook

Post a comment