THE IMPACT OF MOLECULAR DIAGNOSIS ON FAMILIAL COLORECTAL-CANCER

We have shown the impact of molecular diagnostics related to mutation detection in an extensive family with a strong history of colorectal c ancer. The nature and presentation of the cancers suggested that hered itary nonpolyposis colorectal cancer was the most likely cause. The st rategies employed have enabled the detection and characterisation of t he causative mutation in the proband and predictive testing in the rem aining relatives where requested. Using the chemical cleavage of misma tches technique and direct sequencing, the MSH2 and MLH1 genes of the proband were investigated. A single base substitution, C --> T at nucl eotide 350, codon 117, of the MLH1 gene was identified. Across the fam ily pedigree at specific points, 22 other relatives have been tested f or the mutation by direct DNA sequencing from genomic DNA. Of the tota l of 23 patients tested to date, 11 have the mutation. In conjunction with appropriate genetic counselling, this service has clarified the g enetic status of many individuals within this family. Predictive infor mation provided prior to the development of symptoms enables individua ls to make informed choices regarding disease management and the futur e, removing the anxiety associated with the unknown.