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Major Genetic Syndromes

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

    MMR genes may interact with MYH and increase the risk of CRC. An association between MYH and MSH6 has been reported. Both proteins interact together in base excision repair processes. A study reported a significant increase of MSH6 mutations in monoallelic MYH mutation carriers with CRC compared to noncarriers (11.5% vs. 0%; P = .037).[201]

    Lynch Syndrome (LS)

    Between 1900 and 1990, numerous case reports of families with apparent increases in CRC were reported. As series of such reports accumulated, certain characteristic clinical features emerged: early age at onset; high risk of second primary tumors; preferential involvement of the right colon; improved clinical outcome; and a range of associated extracolonic sites including the endometrium, ovaries, other sites in the GI tract, uroepithelium, brain, and skin (sebaceous tumors). Terms such as Lynch 1 (families with CRC only), Lynch 2 (families with CRC and extracolonic tumors), cancer family syndrome, and later, hereditary nonpolyposis colorectal cancer (HNPCC), were commonly employed.

    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 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.

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