Abstract |
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.
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Authors | Wei-Min Gao, Marjorie Romkes, Richard D Day, Jill M Siegfried, James D Luketich, Hussam H Mady, Mona F Melhem, Phouthone Keohavong |
Journal | Carcinogenesis
(Carcinogenesis)
Vol. 24
Issue 10
Pg. 1671-6
(Oct 2003)
ISSN: 0143-3334 [Print] England |
PMID | 12844488
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- DNA-Binding Proteins
- Proteins
- Transcription Factors
- X-ray Repair Cross Complementing Protein 1
- XRCC1 protein, human
- DNA Helicases
- Xeroderma Pigmentosum Group D Protein
- ERCC2 protein, human
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Topics |
- Alleles
- Carcinoma, Non-Small-Cell Lung
(etiology, genetics)
- DNA Helicases
- DNA Mutational Analysis
- DNA Repair
(genetics)
- DNA-Binding Proteins
(genetics)
- Female
- Genes, p53
- Genotype
- Humans
- Lung Neoplasms
(etiology, genetics)
- Male
- Mutation
- Polymerase Chain Reaction
- Polymorphism, Genetic
- Proteins
(genetics)
- Smoking
(adverse effects)
- Transcription Factors
- X-ray Repair Cross Complementing Protein 1
- Xeroderma Pigmentosum Group D Protein
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