HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER - THE SYNDROME, THE GENES, AND HISTORICAL PERSPECTIVES

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal domi nant disorder characterized by the occurrence within a family of multi ple cases of colorectal cancer in the absence of gastrointestinal poly posis. The prevalence of this syndrome is not yet clear, but it may ac count for 1%-5% of all colorectal cancers. Prior to the identification of the genetic basis of this syndrome, the disease was recognized by the familial aggregation of colorectal cancers that had an early age o f onset, an excess of proximally located, and often multiple, primary tumors, and an excess occurrence of cancers in certain other organs. T he recent description of an abnormality called ''microsatellite instab ility,'' present in almost all cancers from HNPCC patients and in abou t 12%-15% of sporadic cases, led to a series of discoveries that linke d this type of genomic instability to a defect in the DNA mismatch rep air (MMR) system. Independent investigators have identified four HNPCC genes: hMSH2 (a homologue of the prokaryotic DNA MMR gene MutS) and h MLH1, hPMS1, and hPMS2 (all homologues of the prokaryotic DNA MMR gene MutL). Mutations in each of the four genes have been found in the ger mline cells of HNPCC families. A major target for research in this are a is the development of clinically practical screening tests for the g enetic carrier state of HNPCC.