Hereditary colorectal cancer in the general population: from cancer registration to molecular diagnosis

Background-Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common inherited disorders predisposing to cancer. The genes responsi ble for the disease have recently been cloned and characterised; their muta tions induce a generalised genomic instability which is particularly eviden t at microsatellite loci (replication error (RER)+ phenotype). Aims-To investigate how to select individuals and families in the general p opulation who should be screened for constitutional mutations predisposing to colorectal cancer. Patients/Methods-Between 1984 and 1995, 1899 colorectal malignancies in 183 1 patients were registered, and in 1721 of these (9-1%), family trees could be obtained. Patients and families were classified into five categories ac cording to a more or less likely genetic basis: HNPCC; "suspected" HNPCC;; juvenile cases; aspecific cancer aggregation; sporadic cases. In 18 familie s with HNPCC as well as in 18 with suspected HNPCC, microsatellite instabil ity in tumour tissues and constitutional mutations of two DNA mismatch repa ir genes (MSH2 and MLH1) could be evaluated. RER status was studied with fi ve markers (BAT40, D2S123, D18S57, D17S787, and BAT26) in paraffin embedded tissues. Germline mutations of MSH2 or MLH1 genes were assessed on DNA and RNA extracted from lymphomonocytic cells, using reverse transcription poly merase chain reaction, single strand conformation polymorphism analysis, an d direct DNA sequencing. Results-HNPCC represented 2.6% and suspected HNPCC 4.6% of all registered c olorectal neoplasms. Eleven out of 18 HNPCC families (61%) showed microsate llite instability as opposed to four (of 18) suspected HNPCC (22%; p<0.02). Three germline mutations (two in MSH2 and one in MLH1 gene) were found in three different large HNPCC families, whereas no mutations were detected in suspected HNPCC. Conclusions-In this study of cancer genetic epidemiology, data from a tumou r registry were analysed and this ultimately led to the identification and selection of families that should be tested for mutator gene mutations. Wit h the use of a population based approach, the incidence of mutations was ap preciably lower than previously reported and limited to families with full blown HNPCC. It is possible that in most families with a clinical spectrum Of HNPCC (or suspected HNPCC) other DNA mismatch repair genes are involved in the pathogenesis of the disease.