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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...

DNA MMR genes

LS is caused by mutation of one of several DNA MMR genes.[298,299,300,301,302,303,304] The function of these genes is to maintain the fidelity of DNA during replication. The genes that have been implicated in LS include MSH2 (mutS homolog 2) on chromosome 2p22-21;[301,302]MLH1 (mutL homolog 1) on chromosome 3p21;[300]PMS2 (postmeiotic segregation 2) on chromosome 7p22;[304,305] and MSH6 on chromosome 2p16. The genes MSH2 and MLH1 are thought to account for most mutations of the MMR genes found in LS families.[241,306]

A variety of LS-associated mutations in MSH2 and MLH1 have been identified. These include founder mutations in the Ashkenazi Jewish, Finnish, Portuguese, and German American populations.[241,293,307,308,309,310] The wide distribution of the mutations in the two genes preclude simple gene testing assays (i.e., assays that would identify only a few mutations). Commercial testing is available to search for mutations in MSH2, MLH1, MSH6, and most recently for PMS2. Clinical and cost considerations may guide testing strategies. Most commercial genetic testing for MSH2 and MLH1 is done by gene sequencing. Because sequencing fails to detect genomic deletions that are relatively common in LS, methods such as Southern blot or MLPA,[311] for detection of large deletions, are being used.[312] (Refer to the Genetic/Molecular testing for LS section of this summary for more information about issues to be considered in testing for these mutations.)



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.[313]

Genotype-phenotype correlations

MLH1 mutations have been associated with the entire spectrum of malignancies associated with LS.[313] The lifetime risk of CRC in MLH1 mutation carriers is estimated to be 41% to 68%.[215,220,314] The lifetime risk of endometrial cancer is estimated to be approximately 40%.[3,220] Muir-Torre syndrome is less commonly associated with MLH1 mutations than are MSH2 mutations.[239]

Practices and pitfalls in testing

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