The gastrointestinal phenotype of germline biallelic mismatch repair gene mutations

Am J Gastroenterol. 2010 Nov;105(11):2449-56. doi: 10.1038/ajg.2010.215. Epub 2010 Jun 8.


Objectives: A novel cancer syndrome associated with biallelic mismatch repair (MMR) mutations has been described recently. Patients presenting with childhood-onset gastrointestinal (GI) cancers may carry biallelic MMR mutations and have a distinct phenotype from classic Lynch syndrome. The aim of this study was to characterize patients with GI small bowel and/or colorectal cancers (CRCs) who have germline biallelic MMR mutations.

Methods: A search of a Canadian GI cancer registry and literature review to identify patients with biallelic MMR was conducted.

Results: The database identified 237 patients with intestinal cancer diagnosed before the age of 35 years. Five (2.1%) patients had biallelic MMR mutations. Overall, 32 individuals, from 29 families, with biallelic MMR gene mutations and GI cancers were identified by the registry and literature review. Among the 29 patients with CRCs, the mean age of first cancer diagnosis was 16.4 years (range: 5-28). More than one-third of patients had multiple colorectal adenomas (>10 polyps). Six individuals with biallelic MMR gene mutations have been reported with small bowel adenocarcinoma (mean age 20 years (range: 11-41)). Café-au-lait (CAL) macules were reported in 72% and, based on mutation analysis, consanguinity was suspected in 52% of kindred. Of the 29 kindred, 19 (66%) had PMS2 mutations, 6 (21%) had MSH6 mutations, 3 (10%) had MLH1 mutations, and 1 (3%) had MSH2 mutation.

Conclusions: Biallelic MMR mutations are an underrecognized cause of small bowel and colonic cancers in children and young adults. This distinct phenotype includes multiple adenomatous polyps and CAL skin lesions. It is important to identify such patients, so that families can be referred for genetic testing and counseling.

MeSH terms

  • Adolescent
  • Adult
  • Alleles*
  • Child
  • Child, Preschool
  • Colorectal Neoplasms / genetics*
  • DNA Mismatch Repair*
  • DNA Mutational Analysis
  • Databases, Factual
  • Genetic Predisposition to Disease*
  • Germ-Line Mutation*
  • Humans
  • Intestinal Neoplasms / genetics*
  • Intestine, Small
  • Microsatellite Instability
  • Phenotype
  • Registries