title: The XPD variant alleles are associated with increased aromatic DNA adduct level and lung cancer risk.
abstract: The DNA repair protein xeroderma pigmentosum complementation group D (XPD) is involved in the nucleotide excision repair of DNA lesions induced by many tobacco and environmental carcinogens. In order to study the functional impact of the common polymorphisms in XPD exon 10 (G > A, Asp312Asn) and exon 23 (A > C, Lys751Gln), we have genotyped 185 Swedish lung cancer cases (97 smokers and 88 never-smokers) and 162 matched population controls (83 smokers and 79 never-smokers). Presence of one or two variant alleles was associated with increased risk for lung cancer among never-smokers only, in particular younger (<70 years) never-smokers [odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.1-6.5 for exon 10; OR = 3.2, 95% CI = 1.3-8.0 for exon 23, adjusted for age, gender and environmental tobacco smoke]. Aromatic DNA adduct level (AL) in peripheral lymphocytes was found to be similar between cases and controls, but significantly increased by current or recent smoking. Overall, there was a significant trend for increasing AL with increasing number of variant alleles in exon 10 (P = 0.02) or in exon 23 (P = 0.001). In addition, subjects with the combined exon 10 AA and exon 23 CC genotype showed a significantly higher AL compared with all those with any of the other genotypes (P = 0.02). We conclude that the XPD variant alleles may be associated with reduced repair of aromatic DNA adducts in general and increased lung cancer risk among never-smokers.
authors.affiliation: Department of Biosciences at Novum, Karolinska Institute, S-141 57 Huddinge, Sweden. saimei.hou@cnt.ki.se
authors.forename: Sai-Mei
authors.initials: SM
authors.lastname: Hou
authors.forename: Susann
authors.initials: S
authors.lastname: Fält
authors.forename: Sabrina
authors.initials: S
authors.lastname: Angelini
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.forename: Fredrik
authors.initials: F
authors.lastname: Nyberg
authors.forename: Bo
authors.initials: B
authors.lastname: Lambert
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000368:Aged; D000483:Alleles; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D002855:Chromatography, Thin Layer; D003062:Codon; D018736:DNA Adducts; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D005091:Exons; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics*; D012307:Risk Factors; D012907:Smoking; D014157:Transcription Factors; D051759:Xeroderma Pigmentosum Group D Protein
chemical_list: D003062:Codon; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D011506:Proteins; D014157:Transcription Factors; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human