Association of the DNA repair gene XPD Asp312Asn polymorphism with p53 gene mutations in tobacco-related non-small cell lung cancer.
Lung cancer, a disease related mostly to tobacco smoke exposure and a leading cause of cancer-related death in industrialized countries, is frequently associated with mutations in the p53 tumor suppressor gene. Genetic differences resulting in inter-individual variation in DNA repair capacity may in part account for susceptibility of a cell to genotoxic agents leading to somatic mutations, including p53 mutations, and eventual transformation of a normal cell into a malignant phenotype. The objective of this study is to investigate the relationship between the polymorphisms of two DNA repair genes, the nucleotide excision repair xeroderma pigmentosum group D (XPD) gene (codons 312 and 751) and the base excision repair X-ray repair cross-complementing group 1 (XRCC1) gene (codon 399), and p53 mutations among lung cancer patients. Lung tumors from 204 smokers with non-small cell lung cancer (NSCLC) were analyzed for mutations in exons 5-8 of the p53 gene and genotypes of XPD and XRCC1. p53 mutations were found in 20% (40/204) of the patients. Patients with the XPD codon 312 Asn allele were less likely to have p53 mutations (13.8%) than XPD 312 Asp/Asp (27.3%) [odds ratio (OR) 0.43, 95% confidence interval (CI) 0.20-0.89, P = 0.023]. No association was found between p53 mutations and either XPD Lys751Gln or XRCC1 Arg399Gln. However, the p53 mutation frequency increased with the increased number of the combined genotypes among XPD 312WT (Asp/Asp), XPD 751VT (Lys/Gln or Gln/Gln) or XRCC1 399VT (Arg/Gln or Gln/Gln) (P = 0.01, trend test). These results suggest that individuals who smoke and have the XPD codon 312 Asp/Asp genotype may be at a greater risk of p53 mutations, especially if combined with other polymorphisms that may result in deficient DNA repair.
Gao
Wei-Min
WM
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Romkes
Marjorie
M
Day
Richard D
RD
Siegfried
Jill M
JM
Luketich
James D
JD
Mady
Hussam H
HH
Melhem
Mona F
MF
Keohavong
Phouthone
P
D000483:Alleles; D002289:Carcinoma, Non-Small-Cell Lung / Q000209:etiology / Q000235:genetics*; D004265:DNA Helicases; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D016158:Genes, p53; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics*; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects*; D014157:Transcription Factors; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein
D004268:DNA-Binding Proteins; D011506:Proteins; D014157:Transcription Factors; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human