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

Table 8. Clinical Practice Guidelines for Diagnosis and Colon Surveillance of Familial Adenomatous Polyposis (FAP) continued...

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 the first HNPCC gene was sequenced, MSH2, it was evident (from the somatic mutation patterns in the tumors) that a family of genes, the MMR family, was likely involved. Shortly thereafter, additional MMR genes were identified, including MLH1, MSH6, and PMS2.

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 immunohistochemistry (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; the sporadic nature of these cases can be confirmed by concurrent detection of somatic BRAF mutations in CRC tumor tissue.

Mutational testing for germline alterations has been somewhat disappointing, as no more than half of suspected HNPCC cases have detectable pathologic mutations. Because of this, and the lack of sufficiently specific clinical features, various genetic screening strategies have emerged to improve the yield of genetic testing. A sufficiently compelling family history, ideally complemented by the presence of MSI, warrants mutational testing, and most clinical practice guidelines provide for such an approach. The Bethesda guidelines are a combination of clinical, pathologic, and family history features that are sufficiently predictive to warrant MSI/IHC screening. Computer risk-assessment profiles have been developed to do this same work more quantifiably and can estimate mutation risk likelihood with or without the intermediate step of using MSI/IHC.

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