The impact of molecular genetics on screening,of hereditary non-polyposis colorectal cancer

Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant precancerous condition accounting for about 2-5% of colorectal cancers. In addition, the risk to develop extracolonic malignancies is markedly elevated in affected persons. HNPCC is caused by germline mutations in one of at least five genes coding for proteins which build up the human mismatch repair (MMR) complex. This complex (among others) cares for stability of the genome during cell division. Mutations in one of the MMR genes lead to loss of repair capacity of the MMR complex and subsequently to a type of DNA instability which is called microsatellite instability (MSI). Identification of the MMR genes enabled the identification of HNPCC patients, which is hampered by lack of an unambiguous phenotype of the disease. Thus, it helped also with the clinical definition of HNPCC (e. g., which extracolonic tumours belong to the syndrome and which do not). Furthermore, surveillance in persons at risk for HNPCC could be clearly improved. Identification of the MMR genes and understanding of their function, on the other side, has led to (in expansion of our knowledge about colorectal carcinogenesis. Not only tumours in HNPCC patients, but zip to 20% of sporadic colorectal cancers are caused by defects of the mismatch repair complex. We now know that these tumours develop difftrently from the remaining 80% of CRC. In the future, these differences may even influence our treatment.