UNICRYPTAL LOSS OF HETEROZYGOSITY IN HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER

DNA mismatch repair genes are responsible for the condition hereditary non-polyposis colorectal cancer (HNPCC). Genomic destabilization caus ed by failure of DNA mismatch repair leads to the progressive accumula tion of somatic mutations and so to accelerated oncogenesis. The aim o f this study was to document the rate of background mutational activit y in the normal colorectal mucosa of subjects with HNPCC. A naturally occurring model utilizing a genetic polymorphism (O-acetyltransferase) allows the development of unicryptal loss of heterozygosity (LOH) to be detected by means of mild PAS histochemistry acid quantified. The r ate of unicryptal LOH was measured in informative and affected members of 3 HNPCC families and found to be within the expected range. This r esult is consistent with the finding that normal cells in HNPCC subjec ts are DNA repair proficient and supports the view that the mutational effects of the HNPCC gene occur selectively within adenomatous epithe lium and serve to accelerate the adenoma-carcinoma sequence.