Polymorphisms in base-excision repair and nucleotide-excision repair genes in relation to lung cancer risk
Faculty of Medicine and Health Sciences
Engineering sciences. Technology
Mutation research. Genetic toxicology and environmental mutagenesis. - Amsterdam
, p. 101-110
Polymorphisms in DNA repair genes may be associated with differences in DNA repair capacity, thereby influencing the individual susceptibility to smoking-related cancer. We investigated the association of 10 base-excision and nucleotide-excision repair gene polymorphisms (XRCCI-77 T/C, Arg 194Trp, Arg28OHis and Arg399Gln; APEI Aspl48Glu; OGG1 Ser326Cys; XPA-4 G/A; XPC PAT: XPD Asp312Asn and Lys75 I Gln) with lung cancer risk in Caucasians. Genotypes were determined by PCR-RFLP and PCR-single base extension assays in 110 lung cancer patients and 110 age- and sex-matched controls, and the results were analyzed using logistic regression adjusted for relevant covariates. A significant association between the APE1 Asp 148Glu polymorphism and lung cancer risk was found, with adjusted odds ratios (OR) of 3.38 (p = 0.001) for the Asp/Glu genotype and 2.39 (P = 0.038) for the Glu/Glu genotype. Gene-smoking interaction analyses revealed a statistically significant interaction between cumulative cigarette smoking and the XRCCl Arg399Gln and XPD Lys75 I Gln polymorphisms: these polymorphisms were significantly associated with lung cancer in nonsmokers and light smokers (< 25 PY, OR = 4.92, p = 0.021 for XRCCl 399 Gln/Gln; OR = 3.62, p = 0.049 for XPD 751 Gln/Gln), but not in heavy smokers (>= 25 PY; OR = 0.68, p = 0.566 for XRCCl 399 GWGln; OR = 0.46, p = 0.295 for XPD 751 Gln/Gln). Both the XRCCl Arg 194Trp and Arg28OHis as well as the OGG1 Ser326Cys heterozygous genotypes were associated with a significantly reduced risk for lung cancer (OR = 0.32, p = 0.024; OR = 0.25, p = 0.028; OR = 0.51, p = 0.033, respectively). No associations with lung cancer risk were found for the XRCCl-77 T/C, the XPA -4 G/A and the XPC PAT polymorphisms. In conclusion, the APEI Aspl48Glu polymorphism is highly predictive for lung cancer, and cumulative cigarette smoking modifies the associations between the XRCCl Arg399Gln and the XPD Lys75 I Gln polymorphisms and lung cancer risk. (c) 2007 Elsevier B.V. All rights reserved.