Cancer risk in a cohort of subjects carrying a single mismatch repair gene mutation

Fam Cancer. 2009;8(4):519-23. doi: 10.1007/s10689-009-9281-5. Epub 2009 Aug 18.


Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant condition, caused by germline mutations in the mismatch repair genes, that presents with colorectal cancers at a young age, as well as extracolonic tumours. One of the causative mutations is the C1528T (Exon 13) mutation of the MLH1 gene. The purpose of this study is to document the cancer risk for subjects who carry this mutation. This is a prospective cohort study of 200 subjects who carry this mutation. We calculated the risk of developing colorectal cancer only in those subjects who had not undergone surveillance colonoscopy. The incidence of extracolonic cancers (for which surveillance is not routinely offered) was determined for the entire cohort. The results of the study are among the 71 subjects who did not undergo surveillance colonoscopy, colorectal cancers occurred in 36 (51%). They occurred at a median age of 44 years (range 17-73). Using Kaplan-Meier estimates, the risk of developing a colorectal cancer by age 65 was 92%. Eighteen subjects in the cohort of 200 were diagnosed with extracolonic tumours. The most common extracolonic malignancies were breast (6/98 women) and endometrial (3/98 women). Thus this mutation has a high penetrance for colorectal cancer, but is not associated with a high risk of developing extracolonic malignancies.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Breast Neoplasms / epidemiology
  • Breast Neoplasms / genetics
  • Colorectal Neoplasms / epidemiology*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / complications
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics
  • DNA Mismatch Repair / genetics
  • Endometrial Neoplasms / epidemiology
  • Endometrial Neoplasms / genetics
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Middle Aged
  • MutL Protein Homolog 1
  • Mutation
  • Nuclear Proteins / genetics*
  • Risk Factors
  • Young Adult


  • Adaptor Proteins, Signal Transducing
  • MLH1 protein, human
  • Nuclear Proteins
  • MutL Protein Homolog 1