The genetics of HNPCC: application to diagnosis and screening

Hereditary nonpolyposis colorectal cancer syndrome (HNPCC; Lynch Syndrome) is the most common form of hereditary colorectal cancers. Predisposed individuals have increased lifetime risk of developing colorectal, endometrial and other cancers. The syndrome is primarily due to heterozygous germline mutations in one of the mismatch repair genes; mainly MLH1, MSH2, MSH6 and PMS2. The resulting mismatch repair deficiency leads to microsatellite instability which is the hallmark of tumors arising within this syndrome, as well as a variable proportion of sporadic tumors. Diagnostic guidelines and criteria for molecular testing of suspected families have been proposed and are continuously updated. However, not all families fulfilling these criteria show mutations in mismatch repair genes and/or microsatellite instability implicating other, as yet unknown, carcinogenic mechanisms and predisposition genes. This subset of tumors is the focus of current clinical and molecular research. This review addresses recent advances in the field of HNPCC research and their applications in the management of affected individuals and families.