Molecular epidemiology of human cancer risk: gene-environment interactions andp53 mutation spectrum in human lung cancer

Bennett, William P.; Hussain, S. Perwez; Vähäkangas, Kirsi; Khan, Mohammed A.; Shields, Peter G.; Harris, Curtis C.

doi:10.1002/(sici)1096-9896(199901)187:1<8::aid-path232>3.0.co;2-y

Cited by 175 publications

(90 citation statements)

References 85 publications

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“…In support of this model, elevated GO content in peripheral leukocyte and lung tissue DNA was observed in lung cancer patients and smokers, suggesting a general increase of oxidative DNA damage (30 -32). Increased G to T mutations (ϳ30%) in p53 in lung tumors from smokers are also observed (33). Here, we demonstrate that deficiencies in the oxidative DNA damage repair genes, Myh and Ogg1, result in lung tumor formation and K-ras activation through G to T mutations at codon12.…”

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Deficiencies in Mouse Myh and Ogg1 Result in Tumor Predisposition and G to T Mutations in Codon 12 of the K-Ras Oncogene in Lung Tumors

et al. 2004

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Oxidative DNA damage is unavoidably and continuously generated by oxidant byproducts of normal cellular metabolism. The DNA damage repair genes, mutY and mutM, prevent G to T mutations caused by reactive oxygen species in Escherichia coli, but it has remained debatable whether deficiencies in their mammalian counterparts, Myh and Ogg1, are directly involved in tumorigenesis. Here, we demonstrate that deficiencies in Myh and Ogg1 predispose 65.7% of mice to tumors, predominantly lung and ovarian tumors, and lymphomas. Remarkably, subsequent analyses identified G to T mutations in 75% of the lung tumors at an activating hot spot, codon 12, of the K-ras oncogene, but none in their adjacent normal tissues. Moreover, malignant lung tumors were increased with combined heterozygosity of Msh2, a mismatch repair gene involved in oxidative DNA damage repair as well. Thus, oxidative DNA damage appears to play a causal role in tumorigenesis, and codon 12 of K-ras is likely to be an important downstream target in lung tumorigenesis. The multiple oxidative repair genes are required to prevent mutagenesis and tumor formation. The mice described here provide a valuable model for studying the mechanisms of oxidative DNA damage in tumorigenesis and investigating preventive or therapeutic approaches.

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Deficiencies in Mouse Myh and Ogg1 Result in Tumor Predisposition and G to T Mutations in Codon 12 of the K-Ras Oncogene in Lung Tumors

et al. 2004

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“…For example it has been established that exposure to cigarette smoke is correlated with G:C to T:A transversion with a DNA coding strand bias and a reduced frequency of G:C4A:T. The DNA coding strand bias is consistent with preferential repair of the transcribed strand (Hanawalt, 1987). Moreover G:C?A:T transitions are common in colon cancer but less frequent in hepatocellular carcinomas (Harris and Hollstein, 1993;Bennett et al, 1999;Hollstein et al, 1996).…”

Section: Other Biochemical Activities Of P53mentioning

confidence: 99%

Twenty years of p53 research: structural and functional aspects of the p53 protein

1999

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“…While the influence of the 5-methyl group in cytosine in a meC-G sequence context on the physical characteristics of double-stranded DNA are not large, it can have a substantial impact on (1) 49,50 Indeed, the occurrence of mutation hot spots in codons 157, 248, and 273 have been associated with an enhanced reactivity of PAH metabolites such as B[a]PDE. 17,20,21,51,52 While this view has been challenged, 53,54 there is accumulating in vitro evidence that the methylation of cytosine in CpG dinucleotide steps indeed enhances the reactivity of B[a]PDE with the guanine residue in meCpG sequence contexts.…”

Section: Discussionmentioning

confidence: 99%

Methylation of Cytosine at C5 in a CpG Sequence Context Causes a Conformational Switch of a Benzo[a]pyrene diol epoxide-N2-guanine Adduct in DNA from a Minor Groove Alignment to Intercalation with Base Displacement

Zhang

Lin

Huang

et al. 2005

Journal of Molecular Biology

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It is well known that CpG dinucleotide steps in DNA, which are highly methylated at the 5-position of cytosine (meC) in human tissues, exhibit a disproportionate number of mutations within certain codons of the p53 gene. There is ample published evidence indicating that the reactivity of guanine with anti-B[a]PDE (a metabolite of the environmental carcinogen benzo[a]pyrene) at CpG mutation hot spots is enhanced by the methylation of the cytosine residue flanking the target guanine residue on the 5′-side. In this work we demonstrate that such a methylation can also dramatically affect the conformational characteristics of an adduct derived HHS Public Access

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Molecular epidemiology of human cancer risk: gene-environment interactions andp53 mutation spectrum in human lung cancer

Cited by 175 publications

References 85 publications

Deficiencies in Mouse Myh and Ogg1 Result in Tumor Predisposition and G to T Mutations in Codon 12 of the K-Ras Oncogene in Lung Tumors

Deficiencies in Mouse Myh and Ogg1 Result in Tumor Predisposition and G to T Mutations in Codon 12 of the K-Ras Oncogene in Lung Tumors

Twenty years of p53 research: structural and functional aspects of the p53 protein

Methylation of Cytosine at C5 in a CpG Sequence Context Causes a Conformational Switch of a Benzo[a]pyrene diol epoxide-N2-guanine Adduct in DNA from a Minor Groove Alignment to Intercalation with Base Displacement

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