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

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.

XPD Lys751Gln polymorphism in the etiology and outcome of childhood acute myeloid leukemia: a Children's Oncology Group report

“…12,13 Several single nucleotide polymorphisms, including an adenine (A) to cytosine (C) (A 3 C) transition, which leads to Lys751Gln in exon 23 of the XPD gene, have been shown to be associated with elevated frequency of chromosomal aberrations and a variety of environmentally induced cancers in adults. [14][15][16][17] There is also evidence that dysregulation of DNA repair proteins and NER pathways may be involved in pathogenesis and prognosis of some myeloid leukemia.…”

Genetic polymorphisms in the DNA repair genes XPD and XRCC1, p53 gene mutations and bladder cancer risk

“…In our previous studies, we hypothesized that if there were functional relevance for the polymorphic DNA repair enzymes in the removal of DNA damages, we would detect differences in p53 mutation frequencies in lung tumors of smoking and/or non-smoking lung cancer patients (43,45). We observed a significant association of p53 mutation frequencies and nucleotide excision repair polymorphisms of XPD in smoking non-small cell lung cancer patients (43) Table I.…”

“…Furthermore, the p53 mutation frequency increased with an increasing number of combined genotypes associated with a lower DNA repair capacity of XPD and XRCC1 399 in lung cancer patients from both smokers and non-smokers (43,45). These results suggested that the presence of certain gene-gene combinations might influence the levels of p53 mutations in lung tumors.…”

“…Each mutant allele appearing on the gel was isolated and further characterized by sequencing, using an ABI PRISM 377 automatic sequencer. The XPD 751 Lys/Gln and XRCC1 399 Arg/Gln polymorphisms were analyzed in genomic DNA using the ABI Prism 7700 sequence detector (TaqMan, Applied Biosystems, Foster City, CA) as described previously (43)(44)(45).…”

Polymorphisms of the DNA repair gene XPD (751) and XRCC1 (399) correlates with risk of hematological malignancies in Turkish population

“…The polymorphisms in XPD-751 gene have been investigated in several diseases. XPD repair gene polymorphisms have been examined especially in colorectal glands and cancers (Yeh et al, 2005;Skjelbred et al, 2006, Artac et al, 2010, breast cancers (Metsola et al, 2005;Shi et al, 2004;Chacko et al, 2005), pancreas cancers (Jiao et al, 2007), bladder cancers (Shen et al, 2003), lung cancers (Hou et al, 2002;Xing et al, 2002;Park et al, 2002 a, b;Gao et al, 2003;Liang et al, 2003;Sreeja et al, 2007), esophageal carcinomas (Yu et al, 2004) and hematological malignancies (Allan et al, 2004;Mehta et al, 2006;Monzo et al, 2006). XRCC1 (X-ray repair cross-complementing group 1) gene one is of the BER repair genes and is located at the 13.2 district of Q part in chromosome 19.…”