MSH6 germline mutations are rare in colorectal cancer families

Int J Cancer. 2003 Nov 20;107(4):571-9. doi: 10.1002/ijc.11415.


Germline mutations in MSH6 can cause HNPCC, which is associated with a tumor phenotype featuring MSI. However, tumors arising in persons with disease-causing mutations of MSH6 may or may not exhibit MSI. We used D-HPLC to screen for germline mutations in the promoter region, the coding region and the 3'-UTR of MSH6. Eighty-four families, enrolled on the basis of Amsterdam I and II criteria (HNPCC families) and less stringent criteria (HNPCC-like families), were tested for MMR gene mutations; 27 families had a disease-causing mutation in MLH1 or MSH2, and the remaining 57 families were tested for mutations in MSH6. Two protein-truncating mutations were identified in each of 2 families fulfilling the Amsterdam I criteria, being present in persons affected with early-onset colorectal cancers exhibiting MSI. Immunohistochemical analysis showed that expression of both MSH2 and MSH6 proteins was lost in the cancer cells of the 2 mutation carriers but only MSH6 protein expression was lost in 2 adenomatous polyps. A third possibly disease-causing mutation was found in a person affected with a tumor that did not exhibit MSI. In addition, we found 4 new polymorphisms and determined that neither of the 2 studied by association analysis conferred susceptibility to colorectal or endometrial cancer. Altogether, our results indicate that disease-causing germline mutations of MSH6 are rare in HNPCC and HNPCC-like families.

Publication types

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

MeSH terms

  • Adult
  • Chromatography, High Pressure Liquid
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / metabolism
  • Colorectal Neoplasms, Hereditary Nonpolyposis / pathology
  • DNA Mutational Analysis
  • DNA Primers / chemistry
  • DNA Repair
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Endometrial Neoplasms / genetics
  • Exons
  • Family
  • Female
  • Genetic Linkage
  • Germ-Line Mutation / genetics*
  • Humans
  • Immunoenzyme Techniques
  • Male
  • Middle Aged
  • MutS Homolog 2 Protein
  • Pedigree
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins / genetics


  • DNA Primers
  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • Proto-Oncogene Proteins
  • MSH2 protein, human
  • MutS Homolog 2 Protein