The L84F polymorphism in the O 6 -Methylguanine-DNA-Methyltransferase (MGMT) gene is associated with increased hypoxanthine phosphoribosyltransferase (HPRT) mutant frequency in lymphocytes of tobacco smokers

Hill, Courtney E.; Wickliffe, Jeffrey K.; Guerin, Adele T.; Kinslow, Carla J.; Wolfe, Kevin J.; Ammenheuser, Marinel M.; Abdel‐Rahman, Sherif Z.

doi:10.1097/fpc.0b013e3281111eb1

Cited by 17 publications

(9 citation statements)

References 54 publications

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“…Recent data showed that the MGMT EX5-25C>T variant was associated with increased mutant frequency in lymphocytes of individuals exposed to alkylating agents (i.e. smokers) (19), suggesting that this evolutionarily conserved, nonsynonymous SNP may alter the phenotype of the MGMT protein resulting in suboptimal repair of O 6 -methylguanine lesions after exposure to alkylating agents. We, however, did not find any significant modification of the SNP effect by consumption of alkylating agents, including smoking and preserved food.…”

Section: Discussionmentioning

confidence: 99%

Variants of DNA Repair Genes and the Risk of Biliary Tract Cancers and Stones: A Population-Based Study in China

Zhang

Huang

Andreotti

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Biliary tract cancers, which encompass tumors of the gallbladder, extrahepatic ducts, and ampulla of Vater, are relatively rare tumors with a high fatality rate. Other than a close link with gallstones, the etiology of biliary tract cancers is poorly understood. We conducted a population-based case-control study in Shanghai, China, to examine whether genetic variants in several DNA repair genes are associated with biliary tract cancers or biliary stones. Genomic DNA from 410 patients with biliary tract cancers (236 gallbladder, 127 bile duct, and 47 ampulla of Vater), 891 patients with biliary stones, and 786 healthy subjects randomly selected from the Shanghai population were genotyped for putative functional single nucleotide polymorphisms in four DNA repair genes (MGMT, RAD23B, CCNH, and XRCC3). Of the five single nucleotide polymorphisms examined, only one (MGMT EX5-25C>T, rs12917) was associated with biliary tract cancer. Independent of gallstones, subjects carrying the CT genotype of the MGMT EX5-25C>T marker had a significantly reduced risk of gallbladder cancer [odds ratio (OR), 0.63; 95% confidence interval (95% CI), 0.41-0.97; P = 0.02] and nonsignificant reduced risks of bile duct (OR, 0.61; 95% CI, 0.35-1.06) and ampulla of Vater (OR, 0.85; 95% CI, 0.39-1.87) cancers. However, this marker was not associated with biliary stones, and the other markers examined were not significantly associated with either biliary tract cancers or stones. Findings from this population-based study in Shanghai suggest that MGMT gene variants may alter susceptibility to biliary tract cancer, particularly gallbladder cancer. Confirmation in future studies, however, is required. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2123 -7)

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Section: Discussionmentioning

confidence: 99%

Variants of DNA Repair Genes and the Risk of Biliary Tract Cancers and Stones: A Population-Based Study in China

Zhang

Huang

Andreotti

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…In the present study, we showed a significant positive correlation between Leu84 (C/C) and c.-56 C/C polymorphism in glioblastomas. Although this is not a perfect linkage disequilibrium, the biological implications of this association should be carefully investigated, since both Leu84 and c.-56 C/C polymorphisms may affect repair activity of O 6 -methylguanine [22,23,26] .…”

Section: Discussionmentioning

confidence: 99%

“…These polymorphisms may affect the primary structure, expression and DNA repair activity of MGMT [20][21][22] . MGMT 84Phe was associated with suboptimal repair of O 6 -methylguanine after exposure to alkylating agents [22,23] . MGMT 143Val affects an amino acid close to the Cys 145 residue at the active site of MGMT [24,25] .…”

Section: Introductionmentioning

confidence: 99%

Promoter Methylation and Polymorphisms of the<i> MGMT</i> Gene in Glioblastomas: A Population-Based Study

et al. 2008

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O⁶-methylguanine-DNA methyltransferase (MGMT) is a repair enzyme that removes promutagenic O⁶-methylguanine adducts in DNA, to protect cells from acquisition of G:C→ A:T mutations. MGMT promoter methylation and polymorphisms may affect MGMT expression and activity. In the present study, we assessed MGMT promoter methylation and polymorphisms (Leu84Phe, Ile143Val, c.–56C>T) in 371 glioblastomas diagnosed at the population level. MGMT methylation was observed in 165 (44%) glioblastomas, with a higher frequency in females than males (53 vs. 39%; p = 0.0106) and in secondary than primary glioblastomas (73 vs. 43%; p = 0.0074). The frequency of TP53 G:C→A:T mutations in glioblastomas with MGMT methylation was 25%, which was significantly higher than that in glioblastomas with MGMT methylation (16%; Fisher exact test; p = 0.0385). MGMT 143 Val allele in glioblastomas was significantly less frequent than in a healthy European Caucasian population, and was associated with longer survival than those with the MGMT 143 Ile allele (hazard ratio 0.70; 95% CI 0.48–1.01). These results suggest that MGMT methylation may be associated with susceptibility to acquire TP53 G:C→A:T mutations, and that MGMT polymorphisms may affect the risk and prognosis of glioblastomas.

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“…Genotyping GSTM1 deletion polymorphisms were determined by multiplex polymerase chain reaction (PCR) (Abdel-Rahman et al, 1996). PCR-RFLP Restriction fragment length polymorphism (PCR-RFLP) analysis was used to identify NQO1*2, CYP1B1*3, and MGMT L84F polymorphisms (Watanabe et al, 2000;Eguchi-Ishimae et al, 2005;Hill et al, 2007;Garcia-Suastegui et al, 2011;Molina et al, 2013).…”

Section: Dna Adduct Determination By 32 P-postlabeling Assaymentioning

confidence: 99%

Prenatal exposure to particulate matter and ozone: Bulky DNA adducts, plasma isoprostanes, allele risk variants, and neonate susceptibility in the Mexico City Metropolitan Area

Maciel‐Ruiz

López‐Rivera

Robles‐Morales

et al. 2019

Environ and Mol Mutagen

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Mexico City's Metropolitan Area (MCMA) includes Mexico City and 60 municipalities of the neighbor states. Inhabitants are exposed to emissions from over five million vehicles and stationary sources of air pollutants such as particulate matter (PM) and ozone. MCMA PM contains elemental carbon and organic carbon (OC). OCs include polycyclic aromatic hydrocarbons (PAHs), many of which induce mutagenic and carcinogenic DNA adducts. Gestational exposure to air pollution has been associated with increased risk of intrauterine growth restriction, preterm birth or low birth weight risk, and PAH‐DNA adducts. These effects also depend on the presence of risk alleles. We investigated the presence of bulky PAH‐DNA adducts, plasma 8‐iso‐PGF2α (8‐iso‐prostaglandin F2α) and risk allele variants in neonates cord blood and their non‐smoking mothers' leucocytes from families that were living in a highly polluted area during 2014–2015. The presence of adducts was significantly associated with both PM2.5 and PM10 levels, mainly during the last trimester of gestation in both neonates and mothers, while the last month of pregnancy was significant for the association between ozone levels and maternal plasma 8‐iso‐PGF2α. Fetal CYP1B1*3 risk allele was associated with increased adduct levels in neonates while the presence of the maternal allele significantly reduced the levels of fetal adducts. Maternal NQO1*2 was associated with lower maternal levels of adducts. Our findings suggest the need to reduce actual PM limits in MCMA. We did not observe a clear association between PM and/or adduct levels and neonate weight, length, body mass index, Apgar or Capurro score. Environ. Mol. Mutagen. 60:428–442, 2019. © 2019 Wiley Periodicals, Inc.

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The L84F polymorphism in the O 6 -Methylguanine-DNA-Methyltransferase (MGMT) gene is associated with increased hypoxanthine phosphoribosyltransferase (HPRT) mutant frequency in lymphocytes of tobacco smokers

Abstract: These new data suggest that the 84F coding single nucleotide polymorphism may alter the phenotype of the MGMT protein, resulting in suboptimal repair of O-methylguanine lesions after exposure to alkylating agents.

Cited by 17 publications

References 54 publications

Variants of DNA Repair Genes and the Risk of Biliary Tract Cancers and Stones: A Population-Based Study in China

Variants of DNA Repair Genes and the Risk of Biliary Tract Cancers and Stones: A Population-Based Study in China

Promoter Methylation and Polymorphisms of the<i> MGMT</i> Gene in Glioblastomas: A Population-Based Study

Prenatal exposure to particulate matter and ozone: Bulky DNA adducts, plasma isoprostanes, allele risk variants, and neonate susceptibility in the Mexico City Metropolitan Area

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