Influence of selection criteria on mutation detection in patients with hereditary nonpolyposis colorectal cancer

BACKGROUND. Hereditary nonpolyposis colorectal cancer (HNPCC) is linked gen etically to mutations in DNA mismatch repair (MMR) genes. Because a deficie ncy in MMR does not predict a specific phenotype, the original selection cr iteria may be too restrictive in identifying additional families. The curre nt study was performed to determine whether a relaxation of the Amsterdam c riteria (AC) could be applied to identify more families associated with DNA MMR. METHODS. Twenty-eight unrelated Swiss families (15 complying with the AC an d 13 fulfilling extended criteria [EC] to include other tumors of the HNPCC spectrum as well) were screened for mutations in the MMR genes hMSH2 and h MLH1, using single-stranded conformation polymorphism and direct DNA sequen cing. Microsatellite instability (MSI) was determined in 14 families. A com parison was made between the phenotypic characteristics of the mutation pos itive and mutation negative families. RESULTS. Ten AC families (67%) harbored germline mutations in hMLH1 (6 kind reds) or hMSH2 (4 kindreds). In none of the EC kindreds could an unambiguou s disease-causing mutation be identified. Seven of eight AC families were f ound to display MSI whereas all colorectal carcinomas (CRC) in eight EC kin dreds were MSI stable. CRC patients from mutation positive families had an earlier age at diagnosis (44 years vs. 49 years) and appeared to have a bet ter survival (11.1 years vs. 7.7 years). CONCLUSIONS. Extending the AC to include extracolonic tumors of the HNPCC s pectrum results in a very low mutation detection rate for hMSH2 and hMLH1. The EC families appear to represent an alternative genetic entity not neces sarily related to DNA MMR gene mutations because they do not display MSI. C ancer 1999;85: 2512-8. (C) 1999 American Cancer Society.