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Association between the Risk for Lung Adenocarcinoma and a (–4) G-to-A Polymorphism in the XPA Gene

¹ Department of Tumor Biology, Center of Oncology-M. Sklodowska-Curie Memorial Institute, Gliwice, Poland and Divisions of ² Toxicology and Cancer Risk Factors and ³ Biostatistics, German Cancer Research Center and ⁴ Thoraxklinik Heidelberg-Rohrbach, Heidelberg, Germany

Requests for reprints: Odilia Popanda, Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. Fax: 49-6221-42-3359. E-mail: o.popanda{at}dkfz-heidelberg.de

Polymorphisms of genes coding for DNA repair can affect lung cancer risk. A common single nucleotide (–4) G-to-A polymorphism was identified previously in the 5' untranslated region of the XPA gene. In a case-control study in European Caucasians, the influence of this polymorphism on primary lung cancer risk overall and according to histologic subtypes was investigated. Four hundred sixty-three lung cancer cases (including 204 adenocarcinoma and 212 squamous cell carcinoma) and 460 tumor-free hospital controls were investigated using PCR amplification and melting point analysis of sequence-specific hybridization probes. Odds ratios (OR) were calculated by multiple logistic regression analysis adjusting for age, gender, smoking habits, and occupational exposure and showed a slightly enhanced risk for all lung cancer cases as well as for squamous cell carcinoma and adenocarcinoma cases. Gene-environment interactions were analyzed with respect to smoking and occupational exposure. A nearly 3-fold increased risk for adenocarcinoma associated with the XPA AA genotype was observed for occupationally exposed individuals (OR, 2.95; 95% confidence interval, 1.42-6.14) and for heavy smokers (OR, 2.52; 95% confidence interval, 1.17-5.42). No genotype-dependent increase in OR was found for nonexposed individuals or those smoking <20 pack-years. The significant effect of the XPA polymorphism in heavy smokers and occupationally exposed individuals suggests an important gene-environment interaction for the XPA gene. The underlying mechanisms as to why AA homozygotes are predisposed to lung adenocarcinoma and which specific carcinogens are involved remains to be determined.

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