HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER - MORPHOLOGIES, GENES AND MUTATIONS

Mutations in a human homologue of the yeast DNA mismatch repair gene M SH2 (equivalent to bacterial MutS) cause the condition hereditary non- polyposis colorectal cancer (HNPCC). Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Adenomas are clonal and eac h may serve as a marker of a single initiating mutation. The progressi on of adenomas is marked by increasing size, dysplasia and villosity. These characteristics can be taken as the morphological counterparts o f the stepwise accumulation of mutations implicating oncogenes and tum our suppressor genes. The aim of this study was to link the morphogene sis of hereditary colorectal cancer with recent insights into the role of DNA mismatch repair genes. The frequency and anatomical distributi on of adenomas in at-risk members of HNPCC families was the same as in an autopsy population. This suggests that the HNPCC gene does not ini tiate the process of neoplastic transformation. On the other hand, ade nomas in at-risk members of HNPCC families were more likely to show vi llosity (p < 0.001), high grade dysplasia (p = 0.002) and probably inc reased size (p = 0.15). These findings are consistent with the observa tion that the HNPCC gene causes DNA replication errors to develop and accumulate within neoplastic but not normal tissues. The effect of the HNPCC gene is to accelerate the progression of adenoma to carcinoma, but not to initiate adenoma development.