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Major Genetic Syndromes

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

    Multiple groups have reported that MSH2 and MSH6 carriers have a greater chance of presenting with endometrial cancers before CRCs than do MLH1 carriers.[3,241,297] The average age at diagnosis of endometrial cancers differed with genotype in two studies: age 41 years for MSH2 , age 49 years for MLH1, and age 55 years for MSH6 carriers.[298,299]

    Practices and pitfalls in testing

    In patients with absence of MSH2 and MSH6 protein expression who have undergone genetic testing with no mutation found by the currently available standard techniques, germline mutation testing for EPCAM/TACSTD1 should be considered. It has been reported that approximately 20% of patients with absence of MSH2 and MSH6 protein expression by IHC and no MSH2 or MSH6 mutation identified will have germline deletions in EPCAM/TACSTD1.[300] The latter mechanism accounts for approximately 5% of all LS cases.[300] (Refer to the EPCAM/TACSTD1 section of this summary for more information.)



    Most series show a prevalence of germline MSH6 mutations in approximately 10% of LS families. However, the reported range (5%–52%) is large.[241,244,245,301,302,303,304] This wide variation is likely a result of small sample sizes, referral bias, and ascertainment bias.

    Genotype-phenotype correlations

    The lifetime risk of colon cancer associated with MSH6 mutations is estimated to be between 12% and 22%.[213,215] It appears that the lifetime risk of CRC might be lower in MSH6 carriers than in MSH2 and MLH1 carriers. Initial studies have suggested that inactivating germline mutations of MSH6 might be more frequent in persons with a later average age at onset of CRC whose tumors exhibit a non-MSI-high phenotype.

    One study reported on 146 MSH6 carriers (59 men and 87 women) from 20 families, all of whom had truncating mutations in MSH6. While the prevalence of CRCs by age 70 years was not significantly different between MSH6 and MLH1 or MSH2 carriers (P = .0854), the mean age at diagnosis for colorectal carcinoma in male MSH6 mutation carriers was 55 years (n = 21; range, 26–84 years) versus 43 years and 44 years in MLH1 and MSH2 mutation carriers, respectively. The prevalence of CRC was significantly lower in women with MSH6 germline mutations than in MLH1 or MSH2 carriers (P = .0049). The mean age at diagnosis for colorectal carcinoma in female MSH6 mutation carriers was 57 years (n = 15; range, 41–81 years) versus 43 years and 44 years in MLH1 and MSH2 mutation carriers, respectively.[260]


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