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Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Major Genetic Syndromes

Table 10. Clinical Practice Guidelines for Colon Surveillance of BiallelicMYH-Associated Polyposis (MAP) continued...

By 1990, the need for enhanced surveillance (colonoscopy at an early age and repeated frequently) was recognized. However, the need to limit this aggressive regimen to families most likely to have an inherited susceptibility or "true" HNPCC led to development of the so-called Amsterdam criteria: three or more cases of CRC over two or more generations, with at least one diagnosed before age 50 years, and no evidence of FAP.

At about this same time, a chromosomal abnormality on 5q led to detecting genetic linkage between FAP and this genomic region, from which the APC gene was eventually cloned. This led to searches for similar linkage in HNPCC. The APC gene was one of several genes (along with DCC and MCC) evaluated and to which no HNPCC linkage was found. An extended genome-wide search resulted in the recognition of a candidate chromosome 2 susceptibility locus in large HNPCC families in 1993. Once MSH2, the first HNPCC gene, was sequenced, it was evident (from the somatic mutation patterns in the tumors) that the mismatch repair (MMR) family of genes was likely involved. Shortly thereafter, additional MMR genes were identified, including MLH1, MSH6, and PMS2. These MMR genes were formerly referred to as hMSH2, hMLH1, hMSH6, and hPMS2, with the "h" designating them as human homologs; for simplicity, the "h" was dropped.

Concurrent with the linkage studies, somatic genetic studies of HNPCC tumors showed evidence of characteristic mutations in microsatellite regions of numerous genes, which appeared to be a molecular marker of MMR deficiency. This was characterized with synonyms such as ubiquitous somatic mutations, replication errors, and eventually, the currently employed term microsatellite instability (MSI). In HNPCC-related tumors showing MSI, there is typically loss of immunohistochemical expression for one or more of the proteins associated with the MMR genes. Since IHC is relatively easy to perform, it can serve to complement or even supplant MSI screening of suspected HNPCC cases. Although MSI characterizes nearly all HNPCC tumors, it can also occur sporadically in about 12% of CRCs. These cases clearly do not have the inherited disorder HNPCC, since further studies have shown that the MSI is caused by somatic inactivation of the MLH1 protein by hypermethylation of the MLH1 promoter. In most instances, the sporadic nature of these cases can be confirmed by concurrent detection of somatic BRAF mutations in CRC tumor tissue.

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