Risk for K-ras gene mutations in smoking-induced lung cancer is associated with cytochrome P4501A1 and glutathione S-transferase μ1 polymorphisms

Noda, Naotaka; Matsuzoe, Daisuke; Konno, Toshikazu; Kawahara, Katsunobu; Yamashita, Yuichi; Shirakusa, Takayuki

doi:10.3892/or.12.4.773

Cited by 2 publications

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“…Such accumulation may lead to an increased rate of PAH-DNA adducts formation [191,193], chromosomal aberrations [173] as well as to higher rates of mutations within specific genes involved in control of the cell cycle and differentiation (p53, k-ras, etc.) [194,195]. This in turn may result in start of a carcinogenesis.…”

Section: Glutathione S-transferasesmentioning

confidence: 98%

Polymorphism of selected enzymes involved in detoxification and biotransformation in relation to lung cancer

2007

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Section: Glutathione S-transferasesmentioning

confidence: 98%

Polymorphism of selected enzymes involved in detoxification and biotransformation in relation to lung cancer

2007

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“…42,43 However, to our knowledge, this is the first study showing a link between CYP1A1 methylation and (i) the formation of DNA adducts and (ii) the TP53 or K-ras mutation statuses. Low levels of CYP1A1 enhancer methylation were associated with high levels of hydrophobic DNA adducts in histologically normal lung tissues and the presence of TP53 or K-ras mutation in the corresponding lung tumors.…”

mentioning

confidence: 97%

DNA methylation of the CYP1A1 enhancer is associated with smoking‐induced genetic alterations in human lung

Tekpli

Zienolddiny

Skaug

et al. 2012

Intl Journal of Cancer

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CYP1A1 (cytochrome P4501A1) catalyze the conversion of polycyclic aromatic hydrocarbons into reactive metabolites, which may induce DNA damage. We hypothesized that DNA methylation of the CYP1A1 enhancer could be involved in inter-individual differences in mRNA levels of CYP1A1 or affect the smoking-induced DNA damage in human lung. Using DNA bisulfite conversion and pyrosequencing, we show that DNA methylation of the CYP1A1 enhancer is affected by smoking. In adjacent histologically normal lung from lung cancer patients (n 5 120), low levels of DNA methylation of the CYP1A1 enhancer were related to high levels of smoking-induced hydrophobic DNA adduct (p < 0.03), and to the presence of TP53 or K-ras mutations in the corresponding lung tumors (p < 0.03). We found an inverse correlation between DNA methylation of the CYP1A1 enhancer and mRNA levels in vivo (Spearman r 5 20.54; p < 0.0001). Thus, in lung tumor tissues, the CYP1A1 enhancer hypermethylation was associated with lower mRNA levels compared to adjacent histologically normal tissue (p < 0.0001). In vitro, using a panel of cultured human lung cells, we found hypermethylation of the CYP1A1 enhancer in cancer cell lines and an inverse correlation between DNA methylation and mRNA levels (Spearman r 5 20.53; p 5 0.003). Altogether, our results indicated that low levels of DNA methylation of the CYP1A1 enhancer in histologically normal human lung were associated with high CYP1A1 mRNA levels and with smoking-induced genetic alterations; thus, it may play a role in the initiation of lung carcinogenesis.

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Risk for K-ras gene mutations in smoking-induced lung cancer is associated with cytochrome P4501A1 and glutathione S-transferase μ1 polymorphisms

Cited by 2 publications

References 0 publications

Polymorphism of selected enzymes involved in detoxification and biotransformation in relation to lung cancer

Polymorphism of selected enzymes involved in detoxification and biotransformation in relation to lung cancer

DNA methylation of the CYP1A1 enhancer is associated with smoking‐induced genetic alterations in human lung

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