Carcinogenesis Advance Access published online on August 27, 2004
Carcinogenesis, doi:10.1093/carcin/bgh264
© 2004 by Oxford University Press
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1 Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
* To whom correspondence should be addressed. E-mail: o.popanda{at}dkfz-heidelberg.de.
Several polymorphisms in DNA repair genes have been reported to be associated with lung cancer risk including XPA (-4G/A), XPD (Lys751Gln and Asp312Asn), XRCC1 (Arg399Gln), APE1 (Asp148Glu), and XRCC3 (Thr241Met). As there is little information on combined effects of these variants, polymorphisms were analyzed in a case-control study including 463 lung cancer cases (among them 204 adenocarcinoma and 212 squamous cell carcinoma) and 460 tumor-free hospital controls. Odds ratios (OR) adjusted for age, gender, smoking and occupational exposure were calculated for the variants alone and combinations thereof. For homozygous individuals carrying the Glu variant of APE1, a protective effect was found (OR=0.77, CI=0.51-1.16). Individuals homozygous for the variants XPA (-4A) (OR=1.53, CI=0.94-2.5), XPD 751Gln (OR=1.39, CI=0.90-2.14) XRCC3 or 241Met (OR=1.29, CI=0.85-1.98) showed a slightly higher risk for lung cancer overall. In the subgroup of adenocarcinoma cases, adjusted ORs were found to be increased for individuals homozygous for XPA (-4A) (OR=1.62, CI=0.91-2.88) and XRCC3 241Met (OR=1.65; CI=0.99-2.75). When analyzing combined effects of variant alleles, 54 patients and controls were identified which were homozygous for two or three of the potential risk alleles (i.e. the variants in nucleotide excision repair, XPA (-4A) and XPD 751Gln, and in homologous recombination, XRCC3-241Met). ORs were significantly increased when all patients (OR=2.37; CI=1.26-4.48), patients with squamous cell carcinoma (OR=2.83; CI=1.17-6.85) and with adenocarcinoma (OR=3.05; CI=1.49-6.23) were analyzed. Combinations of polymorphisms in genes involved in the same repair pathway (XPA+XPD or XRCC1+APE1) affected lung cancer risk only in patients with squamous cell carcinoma. These results indicate that lung cancer risk is only moderately increased by single DNA repair gene variants investigated but it is considerably enhanced by specific combinations of variant alleles. Analyses of additional DNA repair gene interactions in larger population-based studies are warranted for identification of high risk subjects.
Revised July 30, 2004
Accepted August 3, 2004
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Specific combinations of DNA repair gene variants and increased risk for non-small cell lung cancer
2 Department of Tumor Biology, Center of Oncology-M. Sklodowska-Curie Memorial Institute, Gliwice, Poland
3 Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
4 Thoraxklinik Heidelberg-Rohrbach, Heidelberg, Germany
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