RECENT DEVELOPMENTS IN HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER

Background: Hereditary non-polyposis colorectal cancer (HNPCC) is char acterized by early onset of colorectal carcinoma (CRC), usually locate d proximally to the splenic flexure and reportedly carrying a better s urvival as compared to sporadic-type CRC. Depending on the absence or presence of extracolonic tumours, particularly carcinomas of the endom etrium, stomach and urinary tract, HNPCC can be divided into Lynch syn dromes I and II, respectively. Although first described in 1913, the e lucidation of the molecular basis of this disease has only recently st arted to unfold, and is reviewed in this article. Methods: Literature survey of published articles. Results: Comparison of HNPCC rumours wit h sporadic-type CRC had already revealed that no significant differenc es were found in APC, Ki-ras and p53 gene alterations. Instead, micros atellite instability was found to be the hallmark of HNPCC being prese nt in 80% of cases compared to only 13% of sporadic type CRC. Since st udies in yeast and bacteria had shown that microsatellite instability resulted from mutations in so-called postreplicative DNA mismatch repa ir genes, it was hypothesized that a similar mechanism might underlie the observed microsatellite instability in HNPCC and, hence, its hered itary character. In due course, four human homologues of yeast and bac terial postreplicative DNA mismatch repair genes were cloned and denot ed hMSH2, hMLH1, hPMS1, and hPMS2. Current estimates suggest that muta tions in hMSH2 account for 50%, in hMLH1 for 30%, in hPMS1 for 5% and in hPMS2 for 5% of HNPCC. Conclusions: Despite many issues still to be resolved, accurate molecular screening tests will in all probability become the gold standard in the diagnosis of HNPCC. As a result, these developments will undoubtedly have profound implications for early de tection and subsequent management of affected individuals.