Journal Article

Association of the DNA repair gene <i>XPD</i> Asp312Asn polymorphism with p53 gene mutations in tobacco-related non-small cell lung cancer

Wei-Min Gao, Marjorie Romkes, Richard D. Day, Jill M. Siegfried, James D. Luketich, Hussam H. Mady, Mona F. Melhem and Phouthone Keohavong

in Carcinogenesis

Volume 24, issue 10, pages 1671-1676
Published in print October 2003 | ISSN: 0143-3334
Published online October 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgg115
Association of the DNA repair gene XPD Asp312Asn polymorphism with p53 gene mutations in tobacco-related non-small cell lung cancer

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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.

Keywords: BER, base excision repair; BDPE, benzo[a]pyrene-diol-epoxides; CI, confidence interval; DRC, DNA repair capacity; MGB, minor groove binder; NER, nucleotide excision repair; NSCLC, non-small cell lung cancer; OR, odds ratio; PARP, poly (ADP-ribose) polymerase; PBL, peripheral blood lymphocyte; PY, pack-year; ROS, reactive oxygen species; SCE, sister chromatid exchange; TFIIH, transcription factor IIH; XPD, xeroderma pigmentosum group D; XRCC, X-ray repair cross-complementing group 1

Journal Article.  4842 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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