Lack of association between Caucasian lung cancer risk and O6-methylguanine-DNA methyltransferase-codon 178 genetic polymorphism

Yang, Mihi; Coles, Brian; Caporaso, Neil E.; Choi, Yunhee; Lang, Nicholas P.; Kadlubar, Fred F.

doi:10.1016/j.lungcan.2003.12.003

Cited by 34 publications

(28 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They seem to have an effect on the function of MGMT, possibly leading to increased cancer risk. Therefore, there have been several case-control studies that evaluated the associations of these three SNPs with risk of bladder, lung, brain, and breast cancers (17)(18)(19)(20)(21)(22)(23)(24). Although modest risks were reported in some studies for MGMT variants, there are no conclusive findings regarding the role of these MGMT genetic variants in cancer etiology because most studies included relatively small sample sizes of cases and controls with mixed ethnic backgrounds and cancer types in different populations.…”

Section: Introductionmentioning

confidence: 99%

Association of Genetic Variants of O6-Methylguanine-DNA Methyltransferase with Risk of Lung Cancer in Non-Hispanic Whites

Luo¹,

Liu²,

Zhang³

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

Association of Genetic Variants of O6-Methylguanine-DNA Methyltransferase with Risk of Lung Cancer in Non-Hispanic Whites

Luo¹,

Liu²,

Zhang³

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

View full text Add to dashboard Cite

“…However, at present, these are not clearly established. There are a substantial number of epidemiological and biochemical reports on the properties of these variants (reviewed in [48]) but these do not provide a consistent picture with some studies showing increased risk of tumor development and others not [19,20,22,23,25,26,29,31,[45][46][47]. This may be a consequence of the small sample size in most of these studies.…”

Section: Discussionmentioning

confidence: 98%

“…In contrast, the I143V/K178R variant is quite common with a frequency of c. 24% (11−28%) in various studies [17][18][19][20][21][22][23][24]27,[29][30][31], and it is active in protecting cells from alkylation damage. Even in individuals with one allele, the very strong selection pressure that is provided under conditions involving treatment with temozolomide or BCNU plus a hAGT inhibitor would select for cells in which a hAGT form resistant to an inhibitor was present.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Differential inactivation of polymorphic variants of human O6-alkylguanine-DNA alkyltransferase

Fang

Loktionova

Moschel

et al. 2008

Biochemical Pharmacology

View full text Add to dashboard Cite

The human DNA repair protein O 6 -alkylguanine-DNA alkyltransferase (hAGT) is an important source of resistance to some therapeutic alkylating agents and attempts to circumvent this resistance by the use of hAGT inhibitors have reached clinical trials. Several human polymorphisms in the MGMT gene that encodes hAGT have been described including L84F and the linked double alteration I143V/K178R. We have investigated the inactivation of these variants and the much rarer variant W65C by O 6 -benzylguanine, which is currently in clinical trials, and a number of other second generation hAGT inhibitors that contain folate derivatives (O 4 -benzylfolic acid, the 3' and 5' folate esters of O 6 -benzyl-2'-deoxyguanosine and the folic acid γ ester of O 6 -(p-hydroxymethyl) benzylguanine). The I143V/K178R variant was resistant to all of these compounds. The resistance was due solely to the I143V change. These results suggest that the frequency of the I143V/K178R variant among patients in the clinical trials with hAGT inhibitors and the correlation with response should be considered.

show abstract

“…The expression level of MGMT in humans varies up to 40-fold (20), and studies have shown that genetic components might explain part of the interindividual variation (21). Several studies have been conducted to investigate the association between MGMT polymorphisms and lung cancer risk, but the results are inconsistent, mainly due to lack of statistical power, because the majority of the studies had under 400 case-control pairs (22)(23)(24)(25)(26)(27). I143V and K178R polymorphisms are in strong linkage disequilibrium.…”

Section: Discussionmentioning

confidence: 99%

Inherited Predisposition of Lung Cancer: A Hierarchical Modeling Approach to DNA Repair and Cell Cycle Control Pathways

Hung

Baragatti

Thomas

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

View full text Add to dashboard Cite

The DNA repair systems maintain the integrity of the human genome and cell cycle checkpoints are a critical component of the cellular response to DNA damage. We hypothesized that genetic variants in DNA repair and cell cycle control pathways will influence the predisposition to lung cancer, and studied 27 variants in 17 DNA repair enzymes and 10 variants in eight cell cycle control genes in 1,604 lung cancer patients and 2,053 controls. To improve the estimation of risks for specific variants, we applied a Bayesian approach in which we allowed the prior knowledge regarding the evolutionary biology and physicochemical properties of the variant to be incorporated into the hierarchical model. Based on the estimation from the hierarchical modeling, subjects who carried OGG1 326C/326C homozygotes, MGMT 143V or 178R, and CHEK2 157I had an odds ratio of lung cancer equal to 1.45 [95% confidence interval (95% CI), 1.05-2.00], 1.18 (95% CI, 1.01-1.40), and 1.58 (95% CI, 1.14-2.17). The association of CHEK2 157I seems to be overestimated in the conventional analysis. Nevertheless, this association seems to be robust in the hierarchical modeling. None of the pathways seem to have a prominent effect. In general, our study supports the notion that sequence variation may explain at least some of the variation of inherited susceptibility. In particular, further investigation of OGG1, MGMT, and CHEK2 focusing on the genetic regions where the present markers are located or the haplotype blocks tightly linked with these markers might be warranted. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2736 -44)

show abstract

Lack of association between Caucasian lung cancer risk and O6-methylguanine-DNA methyltransferase-codon 178 genetic polymorphism

Cited by 34 publications

References 19 publications

Association of Genetic Variants of O6-Methylguanine-DNA Methyltransferase with Risk of Lung Cancer in Non-Hispanic Whites

Association of Genetic Variants of O6-Methylguanine-DNA Methyltransferase with Risk of Lung Cancer in Non-Hispanic Whites

Differential inactivation of polymorphic variants of human O6-alkylguanine-DNA alkyltransferase

Inherited Predisposition of Lung Cancer: A Hierarchical Modeling Approach to DNA Repair and Cell Cycle Control Pathways

Contact Info

Product

Resources

About