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Major Genetic Syndromes

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



    MLH1 and MSH2 make up the majority of LS mutations. Up to 50% of mutation-positive LS families harbor a MLH1 mutation, with some geographic variation.[293]

    Genotype-phenotype correlations

    MLH1 mutations have been associated with the entire spectrum of malignancies associated with LS.[293] The lifetime risk of CRC in MLH1 mutation carriers is estimated to be 41% to 68%.[210,215,294] The lifetime risk of endometrial cancer is estimated to be approximately 40%.[3,215] Muir-Torre syndrome is less commonly associated with MLH1 mutations than are MSH2 mutations.[234]

    Practices and pitfalls in testing

    In contrast to the scenario of MSI associated with loss of expression of MSH2, MSH6 or PMS2, absence of MLH1 expression is not specific to LS. Most instances of absence of MLH1 expression are caused by the sporadic hypermethylation of the MLH1 promoter. Therefore, absent MLH1 expression is less specific for LS than absence of the other MMR proteins. In addition, rare instances of inherited germline MLH1 methylation have added additional complexity to the interpretation of MSI associated with absence of MLH1 expression. (Refer to the Microsatellite instability (MSI) section for more information about germline MLH1 hypermethylation.)



    The prevalence of MSH2 mutations in individuals or families with LS has varied across studies. MSH2 mutations were reported in 38% to 54% of LS families in studies including large cancer registries, cohorts of early-onset CRC (<55 years), and registries around the world.[212,249]

    Genotype-phenotype correlations

    The lifetime risk of colon cancer associated with MSH2 mutations is estimated to be between 48% and 68%.[210,215,294] In a case series of LS patients, those carrying germline MSH2 mutations (49 individuals, 45% females) had a lifetime (cutoff of age 60 years) risk of extracolonic cancers of 48% compared with 11% for MLH1 carriers (56 individuals, 50% females).[295] In addition, the same group reported a significantly higher prevalence of poorly differentiated CRCs (44% for MSH2 carriers vs. 14% for MLH1 carriers; P = .002) and Crohn-like reaction (49% for MSH2 carriers vs. 27% for MLH1 carriers; P = .049). Another study reported no significant differences between the prevalence of colorectal and extracolonic cancers in 22 families with germline MLH1 mutations and in 12 families with germline MSH2 mutations.[296]


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