Background: Hereditary non-polyposis colorectal cancer (HNPCC) is characterized by early onset of colorectal carcinoma (CRC), usually located proximally to the splenic flexure and reportedly carrying a better survival as compared to sporadic-type CRC. Depending on the absence or presence of extracolonic tumours, particularly carcinomas of the endometrium, stomach and urinary tract, HNPCC can be divided into Lynch syndromes I and II, respectively. Although first described in 1913, the elucidation of the molecular basis of this disease has only recently started to unfold, and is reviewed in this article.
Methods: Literature survey of published articles.
Results: Comparison of HNPCC tumours with sporadic-type CRC had already revealed that no significant differences were found in APC, Ki-ras and p53 gene alterations. Instead, microsatellite instability was found to be the hallmark of HNPCC being present in 80% of cases compared to only 13% of sporadic type CRC. Since studies in yeast and bacteria had shown that microsatellite instability resulted from mutations in so-called postreplicative DNA mismatch repair genes, it was hypothesized that a similar mechanism might underlie the observed microsatellite instability in HNPCC and, hence, its hereditary character. In due course, four human homologues of yeast and bacterial postreplicative DNA mismatch repair genes were cloned and denoted hMSH2, hMLH1, hPMS1, and hPMS2. Current estimates suggest that mutations 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 detection and subsequent management of affected individuals.