Article

Al-Tassan N, Chmiel NH, Maynard J, Fleming N, Livingstone AL, Williams GT et al. Inherited variants of MYH associated with somatic G:C->T:A mutations in colorectal tumors. Nat Genet 30: 227-232

Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK.
Nature Genetics (Impact Factor: 29.35). 02/2002; 30(2):227-32. DOI: 10.1038/ng828
Source: PubMed

ABSTRACT

Inherited defects of base excision repair have not been associated with any human genetic disorder, although mutations of the genes mutM and mutY, which function in Escherichia coli base excision repair, lead to increased transversions of G:C to T:A. We have studied family N, which is affected with multiple colorectal adenomas and carcinoma but lacks an inherited mutation of the adenomatous polyposis coli gene (APC) that is associated with familial adenomatous polyposis. Here we show that 11 tumors from 3 affected siblings contain 18 somatic inactivating mutations of APC and that 15 of these mutations are G:C-->A transversions--a significantly greater proportion than is found in sporadic tumors or in tumors associated with familial adenomatous polyposis. Analysis of the human homolog of mutY, MYH, showed that the siblings were compound heterozygotes for the nonconservative missense variants Tyr165Cys and Gly382Asp. These mutations affect residues that are conserved in mutY of E. coli (Tyr82 and Gly253). Tyrosine 82 is located in the pseudo-helix-hairpin-helix (HhH) motif and is predicted to function in mismatch specificity. Assays of adenine glycosylase activity of the Tyr82Cys and Gly253Asp mutant proteins with 8-oxoG:A and G:A substrates show that their activity is reduced significantly. Our findings link the inherited variants in MYH to the pattern of somatic APC mutation in family N and implicate defective base excision repair in predisposition to tumors in humans.

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    • "This is exemplified by the embryonic lethality of mice that possess knockouts of key components of this pathway [154] [155] [156]. A biallelic germline defect within a DNA glycosylase, mutY Homology (MUTYH), was initially found in families that had excess colorectal tumors with somatic mutations in the adenomatous polyposis coli gene [157]. A subsequent larger study revealed that biallelic germline MUTYH defects conferred 93 fold excess risk of colon cancer with penetrance by age 60 [158] [159] and may also confer increased risk for endometrial cancer [160]. "
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    ABSTRACT: Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology.
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    • "This is exemplified by the embryonic lethality of mice that possess knockouts of key components of this pathway [154] [155] [156]. A biallelic germline defect within a DNA glycosylase, mutY Homology (MUTYH), was initially found in families that had excess colorectal tumors with somatic mutations in the adenomatous polyposis coli gene [157]. A subsequent larger study revealed that biallelic germline MUTYH defects conferred 93 fold excess risk of colon cancer with penetrance by age 60 [158] [159] and may also confer increased risk for endometrial cancer [160]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
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    • "We and other groups have reported that mice deficient in these enzymes are prone to developing cancer, indicating a mutator phenotype in somatic cells13141516. MUTYH is also responsible for MUTYH-associated polyposis in humans17. "
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