GERMLINE HNPCC GENE VARIANTS HAVE LITTLE INFLUENCE ON THE RISK FOR SPORADIC COLORECTAL-CANCER

Hereditary non-polyposis colorectal cancer (HNPCC) is a syndrome of in herited bowel and other cancers that has been said to account for up t o 15% of all colorectal carcinomas (CRCs). HNPCC can now be diagnosed at the molecular level by detecting germline mutations in genes involv ed in mismatch repair. A current problem is to determine the prevalenc e of HNPCC mutations in colon cancer patients with limited or no famil y history, especially in cases of early onset. We have identified 50 c ases of non-polyposis colorectal cancer without a family history of CR C or any other HNPCC cancer who presented under the age of 45 years. G ermline HNPCC variants (at the hMSH2 or hMLH1 loci) were detected in a small minority of cases (6%). The variants that we have found may be new or low penetrance mutations, or even polymorphisms. It remains pos sible that some of our sample have an inherited predisposition to CRC that is not caused by HNPCC mutations or by known polyposis syndromes. Our data suggest that most HNPCC mutations occur in families and have high or moderate penetrance. New or low penetrance HNPCC mutations pr obably do not contribute significantly to the risk of colorectal cance r in the general population and probably account for much fewer than 1 5% of all CRCs. Our results question whether mass population genetic s creening programmes are worthwhile for diseases such as HNPCC using cu rrent technology.