Background: Clinical screening is still the first-line approach to identification of families with hereditary non-polyposis colorectal cancer (HNPCC). The need for uniformity of diagnosis of the syndrome, particularly in multicentre studies, led to the establishment of a set of minimum diagnostic criteria, the 'Amsterdam criteria'. It is now known that HNPCC is caused by germline defects in the human mismatch repair genes and DNA predictive testing is possible. Defects in two of the known mismatch repair genes, namely hMSH2 and hMLH1, account for over 90 per cent of mutations found in HNPCC families.
Methods: Ten families were identified with pedigrees suggestive of HNPCC (that is with a possible dominant inheritance of HNPCC), but in which the Amsterdam criteria were not fulfilled. Using the technique of single-strand conformational polymorphism analysis, samples were screened from an affected member of each of these ten kindreds for germline mutations in the genes hMSH2 and hMLH1.
Results: Mutations were identified in six families. Of these, there were three missense, one nonsense, one frameshift and one putative splice-site mutation. Three of the mutations were in hMSH2 and three in hMLH1.
Conclusion: This study demonstrates that all families with a pedigree suggestive of HNPCC should be referred to a geneticist even if the Amsterdam criteria are not fulfilled. A knowledge of the gene carrier status enables targeted surveillance and the possibility of early surgical intervention that could be curative.