FREQUENCY OF GERMLINE HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER GENE-MUTATIONS IN PATIENTS WITH MULTIPLE OR EARLY-ONSET COLORECTAL ADENOMAS

Background-The hereditary non-polyposis colorectal cancer (HNPCC) synd rome is caused by germline mutations in mismatch repair genes and pred isposes individuals to cancers of the colon and other specific sites. On theoretical grounds, it is expected that patients with HNPCC also d evelop more colorectal adenomas than the general population. In essenc e if the mutation rate is raised owing to mutations at a mismatch repa ir locus, more mutations are expected at loci such as APC (adenomatous polyposis coli) and more adenomas will start to grow. Not all data su pport this expectation, however. Aim-To search for germline mutations at HNPCC loci in patients with multiple adenomas. Subjects-Twenty five patients (without known APC mutations) who have developed colorectal adenomas in unusually large numbers and, in some cases, at an early ag e. Methods-Germline APC mutations were excluded using the protein truc tion test for exon 15 and mismatch chemical cleavage analysis for rema ining exons. Germline HNPCC mutations were detected by using PCR and s ingle strand conformation polymorphism analysis. Results-Just one germ line HNPCC mutation was found (4% of cases) and this was of uncertain functional effect. Conclusions-In general, germline HNPCC mutations ar e not responsible for the phenotype of patients with multiple colonic adenomas. It is possible that patients with HNPCC tend to develop aden omas more frequently and earlier than the general population, but that this effect is relatively subtle. These results suggest that individu als with colorectal adenomas only should not strictly be classified as ''affected'' in HNPCC families (although they should certainly not be classified as ''unaffected'' either and may warrant intensive screeni ng). In the absence of a personal or strong family history of colorect al cancer, it is probably not worthwhile performing diagnostic or pred ictive genetic testing for HNPCC mutations in subjects with colorectal adenomas. Although undetected APC mutations may be responsible for so me of the phenotypes in this sample, as yet uncharacterised adenoma pr edisposing genes probably exist.