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Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Colon Cancer Genes

Table 2. Major Genes Associated with Risk of Colorectal Cancer continued...


LS is caused by mutation of one of several DNA MMR genes.[18,19,20,21,22,23,24] 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;[21,22]MLH1 (mutL homolog 1) on chromosome 3p21;[20]PMS2 (postmeiotic segregation 2) on chromosome 7p22;[24,25] 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.[26,27]

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.[27,28,29,30,31,32] 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 multiplex ligation-dependent probe amplification (MLPA),[33] for detection of large deletions, are being used.[34] (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.)

Peutz-Jeghers Gene(s)

Peutz-Jeghers syndrome (PJS) is characterized by mucocutaneous pigmentation and gastrointestinal polyposis and is caused by mutations in the STK11 (also named LKB1) tumor suppressor gene located on chromosome 19p13.[35,36] Unlike the adenomas seen in FAP, the polyps arising in PJS are hamartomas. Studies of the hamartomatous polyps and cancers of PJS show allelic imbalance (loss of heterozygosity [LOH]) consistent with the two-hit hypothesis, demonstrating that STK11 is a tumor suppressor gene.[37,38] However, heterozygous STK11 knockout mice develop hamartomas without inactivation of the remaining wild-type allele, suggesting that haploinsufficiency is sufficient for initial tumor development in PJS.[39] Subsequently, the cancers that develop in STK11 +/- mice do show LOH;[40] indeed, compound mutant mice heterozygous for mutations in STK11 +/- and homozygous for mutations in TP53 -/- have accelerated development of both hamartomas and cancers.[41]

Germline mutations of the STK11 gene represent a spectrum of nonsense, frameshift, and missense mutations, and splice-site variants and large deletions.[42,43] Approximately 85% of mutations are localized to regions of the kinase domain of the expressed protein, and no germline mutations have been reported in exon 9. No strong genotype-phenotype correlations have been identified.[42]

One gene (STK11) has been unequivocally demonstrated to cause PJS. Although earlier estimates using direct DNA sequencing showed a 50% mutation detection rate in STK11, studies adding techniques to detect large deletions have found mutations in up to 94% of individuals meeting clinical criteria for PJS.[43,44,45] Given the results of these studies, it is unlikely that other major genes cause PJS.


WebMD Public Information from the National Cancer Institute

Last Updated: February 25, 2014
This information is not intended to replace the advice of a doctor. Healthwise disclaims any liability for the decisions you make based on this information.
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