GENETIC TESTING IS IMPORTANT IN FAMILIES WITH A HISTORY SUGGESTIVE OFHEREDITARY NONPOLYPOSIS COLORECTAL-CANCER EVEN IF THE AMSTERDAM CRITERIA ARE NOT FULFILLED

Background Clinical screening is still the first-line approach to iden tification of families with hereditary non-polyposis colorectal cancer (HNPCC). The need for uniformity of diagnosis of the syndrome, partic ularly in multicentre studies, led to the establishment of a set of mi nimum diagnostic criteria, the 'Amsterdam criteria'. It is now known t hat HNPCC is caused by germline defects in the human mismatch repair g enes and DNA predictive testing is possible. Defects in two of the kno wn mismatch repair genes, namely hMSH2 and hMLH1, account for over 90 per cent of mutations found in HNPCC families. Methods Ten families we re identified with pedigrees suggestive of HNPCC (that is with a possi ble dominant inheritance of HNPCC), but in which the Amsterdam criteri a were not fulfilled. Using the technique of single-strand conformatio nal polymorphism analysis, samples were screened from an affected memb er of each of these ten kindreds for germline mutations in the genes h MSH2 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 a nd three in hMLH1. Conclusion This study demonstrates that all familie s with a pedigree suggestive of HNPCC should be referred to a genetici st even if the Amsterdam criteria are not fulfilled. A knowledge of th e gene carrier status enables targeted surveillance and the possibilit y of early surgical intervention that could be curative.