title: Polymorphisms in base-excision repair and nucleotide-excision repair genes in relation to lung cancer risk.
abstract: 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 (XRCC1 -77 T/C, Arg194Trp, Arg280His and Arg399Gln; APE1 Asp148Glu; OGG1 Ser326Cys; XPA -4 G/A; XPC PAT; XPD Asp312Asn and Lys751Gln) 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 Asp148Glu 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 XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms: these polymorphisms were significantly associated with lung cancer in nonsmokers and light smokers (<25 PY; OR=4.92, p=0.021 for XRCC1 399 Gln/Gln; OR=3.62, p=0.049 for XPD 751 Gln/Gln), but not in heavy smokers (> or =25 PY; OR=0.68, p=0.566 for XRCC1 399 Gln/Gln; OR=0.46, p=0.295 for XPD 751 Gln/Gln). Both the XRCC1 Arg194Trp and Arg280His 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 XRCC1 -77 T/C, the XPA -4 G/A and the XPC PAT polymorphisms. In conclusion, the APE1 Asp148Glu polymorphism is highly predictive for lung cancer, and cumulative cigarette smoking modifies the associations between the XRCC1 Arg399Gln and the XPD Lys751Gln polymorphisms and lung cancer risk.
authors.affiliation: Department of Anatomy, Embryology, Histology and Medical Physics, Ghent University, Proeftuinstraat 86, B-9000 Gent, Belgium. kim.deruyck@ugent.be
authors.forename: Kim
authors.initials: K
authors.lastname: De Ruyck
authors.forename: Marcin
authors.initials: M
authors.lastname: Szaumkessel
authors.forename: Isabelle
authors.initials: I
authors.lastname: De Rudder
authors.forename: Annelore
authors.initials: A
authors.lastname: Dehoorne
authors.forename: Anne
authors.initials: A
authors.lastname: Vral
authors.forename: Kathleen
authors.initials: K
authors.lastname: Claes
authors.forename: Anja
authors.initials: A
authors.lastname: Velghe
authors.forename: Jan
authors.initials: J
authors.lastname: Van Meerbeeck
authors.forename: Hubert
authors.initials: H
authors.lastname: Thierens
mesh_terms: D001483:Base Sequence; D045647:DNA Glycosylases; D017931:DNA Primers; D004260:DNA Repair / Q000235:genetics*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics; D009699:N-Glycosyl Hydrolases / Q000235:genetics; D011110:Polymorphism, Genetic; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; C479058:oxoguanine glycosylase 1, human; D051759:Xeroderma Pigmentosum Group D Protein; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; C497292:ERCC2 protein, human