Hereditary nonpolyposis colorectal cancer (HNPCC) is a common autosomal dominant cancer-susceptibility condition characterized by early onset colorectal cancer. Germ-line mutations in one of four DNA mismatch repair (MMR) genes, hMSH2, hMLH1, hPMS1, or hPMS2, are known to cause HNPCC. Although many mutations in these genes have been found in HNPCC kindreds complying with the so-called Amsterdam criteria, little is known about the involvement of these genes in families not satisfying these criteria but showing clear-cut familial clustering of colorectal cancer and other cancers. Here, we applied denaturing gradient-gel electrophoresis to screen for hMSH2 and hMLH1 mutations in two sets of HNPCC families, one set comprising families strictly complying with the Amsterdam criteria and another set in which at least one of the criteria was not satisfied. Interestingly, hMSH2 and hMLH1 mutations were found in 49% of the kindreds fully complying with the Amsterdam criteria, whereas a disease-causing mutation could be identified in only 8% of the families in which the criteria were not satisfied fully. In correspondence with these findings, 4 of 6 colorectal tumors from patients belonging to kindreds meeting the criteria showed microsatellite instability, whereas only 3 of 11 tumors from the other set of families demonstrated this instability. Although the number of tumors included in the study admittedly is small, the frequencies of mutations in the MMR genes show obvious differences between the two clinical sets of families. These results also emphasize the practical importance of the Amsterdam criteria, which provide a valid clinical subdivision between families, on the basis of their chance of carrying an hMSH2 or an hMLH1 mutation, and which bear important consequences for genetic testing and counseling and for the management of colorectal cancer families.

• MeSH
• Adaptor Proteins, Signal Transducing MeSH
• Colorectal Neoplasms, Hereditary Nonpolyposis enzymology   ethnology   genetics   MeSH
• Protein Denaturation MeSH
• DNA-Binding Proteins * MeSH
• Electrophoresis, Polyacrylamide Gel methods   MeSH
• Nucleic Acid Heteroduplexes MeSH
• MutS Homolog 2 Protein MeSH
• Nuclear Proteins MeSH
• Humans MeSH
• Microsatellite Repeats MeSH
• MutL Protein Homolog 1 MeSH
• Neoplasm Proteins genetics   MeSH
• DNA Repair genetics   MeSH
• Proto-Oncogene Proteins genetics   MeSH
• Reference Standards MeSH
• Case-Control Studies MeSH
• Carrier Proteins MeSH
• Germ-Line Mutation * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH
• Denmark MeSH
• Italy MeSH
• Netherlands MeSH