Journal Article

Specific combinations of DNA repair gene variants and increased risk for non-small cell lung cancer

Odilia Popanda, Torsten Schattenberg, Chi Tai Phong, Dorota Butkiewicz, Angela Risch, Lutz Edler, Klaus Kayser, Hendrik Dienemann, Volker Schulz, Peter Drings, Helmut Bartsch and Peter Schmezer

in Carcinogenesis

Volume 25, issue 12, pages 2433-2441
Published in print December 2004 | ISSN: 0143-3334
Published online December 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh264
Specific combinations of DNA repair gene variants and increased risk for non-small cell lung cancer

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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 the 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 (SCC)] 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) or XRCC3 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 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 the combined effects of variant alleles, 54 patients and controls were identified that 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 SCC (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 SCC. 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.

Keywords: AC, adenocarcinoma; BER, base excision repair; CI, confidence intervals; ERCC2, excision repair cross-complementing rodent repair deficiency, complementation group 2 (xeroderma pigmentosum D); NER, nucleotide excision repair; OR, odds ratio; PY, pack years; SCC, squamous cell carcinoma; XP, Xeroderma pigmentosum

Journal Article.  7318 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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