Large-scale investigation of base excision repair genetic polymorphisms and lung cancer risk in a multicenter study.

BACKGROUND Base excision repair (BER) is a highly conserved essential mechanism for maintaining genome integrity. We examined associations among four well-characterized polymorphisms of BER genes (OGG1 Ser326Cys, XRCC1 Arg194Trp, XRCC1 Arg280His, and XRCC1 Arg399Gln) and lung cancer risk. METHODS A total of 2188 patients with lung cancer and 2198 control subjects without lung cancer recruited at 15 centers in six Eastern European countries from February 1998 to October 2002 provided DNA samples for genotype analysis. Genetic polymorphisms were analyzed by the fluorescence 5' exonuclease and Amplifluor assays. Unconditional multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). We estimated the false-positive reporting probability (FPRP) for our results by incorporating a range of prior probabilities that specific polymorphisms are associated with lung cancer risk. All statistical tests were two-sided. RESULTS The overall odds ratio for lung cancer among those with the OGG1 Cys/Cys genotype compared with those with the OGG1 Ser/Ser genotype was 1.34 (95% CI = 0.95 to 1.88); the association was most prominent for adenocarcinoma risk (OR = 1.66, 95% CI = 1.04 to 2.66). Overall, the XRCC1 polymorphisms were not associated with the risk of lung cancer. However, the XRCC1 Arg194Trp and Arg280His variants were each associated with a reduced risk of lung cancer among subjects in the highest quartile of pack-years of smoking compared with common allele homozygotes (ORs of 0.65 [95% CI = 0.46 to 0.93] and 0.56 [95% CI = 0.36 to 0.86], respectively). The associations between the OGG1 Cys/Cys genotype and adenocarcinoma risk and between XRCC1 Arg194Trp polymorphism and lung cancer risk among heavy smokers remained robust given prior probabilities of 25% (FPRP = 0.238) and 10% (FPRP = 0.276), respectively. CONCLUSIONS Our results do not support a major independent role of BER gene polymorphisms in lung cancer risk. However, we cannot exclude the possibility that the OGG1 Ser326Cys and XRCC1 Arg194Trp polymorphisms play minor roles in lung carcinogenesis.

[1]  Christopher I Amos,et al.  Genetic susceptibility to lung cancer: the role of DNA damage and repair. , 2003, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[2]  E. Friedberg,et al.  DNA damage and repair , 2003, Nature.

[3]  H. Sugimura,et al.  HOGG1 Ser326Cys polymorphism and modification by environmental factors of stomach cancer risk in Chinese , 2002, International journal of cancer.

[4]  T. Paz-Elizur,et al.  DNA repair activity for oxidative damage and risk of lung cancer. , 2003, Journal of the National Cancer Institute.

[5]  S. Hirohashi,et al.  Lung Cancer Patients Have Increased 8‐Hydroxydeoxyguanosine Levels in Peripheral Lung Tissue DNA , 1998, Japanese journal of cancer research : Gann.

[6]  M. Tockman,et al.  Polymorphisms of the DNA repair gene XRCC1 and lung cancer risk. , 2001, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[7]  N. Rothman,et al.  Population stratification in epidemiologic studies of common genetic variants and cancer: quantification of bias. , 2000, Journal of the National Cancer Institute.

[8]  D. Bell,et al.  XRCC1 polymorphisms: effects on aflatoxin B1-DNA adducts and glycophorin A variant frequency. , 1999, Cancer research.

[9]  P Vineis,et al.  XRCC1, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects. , 2001, Carcinogenesis.

[10]  L. Marchand,et al.  Association of the hOGG 1 Ser 326 Cys Polymorphism with Lung Cancer Risk 1 , 2002 .

[11]  T. Tsuzuki,et al.  Ogg1 knockout-associated lung tumorigenesis and its suppression by Mth1 gene disruption. , 2003, Cancer research.

[12]  G. Matullo,et al.  DNA adduct levels and DNA repair polymorphisms in traffic‐exposed workers and a general population sample , 2001, International journal of cancer.

[13]  L. Excoffier,et al.  Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. , 1995, Molecular biology and evolution.

[14]  P. Newcomb,et al.  Selection bias in the assessment of gene-environment interaction in case-control studies. , 2003, American journal of epidemiology.

[15]  S. London,et al.  Genetic polymorphism of XRCC1 and lung cancer risk among African-Americans and Caucasians. , 2001, Lung cancer.

[16]  K. Matsuo,et al.  A Limited Association of OGG1 Ser326Cys Polymorphism for Adenocarcinoma of the Lung , 2002, Journal of epidemiology.

[17]  M. Dizdaroglu,et al.  Excision of oxidatively damaged DNA bases by the human α-hOgg1 protein and the polymorphic α-hOgg1(Ser326Cys) protein which is frequently found in human populations , 1999 .

[18]  C. Ulrich,et al.  Polymorphic variation in hOGG1 and risk of cancer: A review of the functional and epidemiologic literature , 2005, Molecular carcinogenesis.

[19]  D. Christiani,et al.  Polymorphisms in the DNA repair genes XRCC1 and ERCC2, smoking, and lung cancer risk. , 2003, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[20]  M. Tockman,et al.  Gene-environment interactions between the codon 194 polymorphism of XRCC1 and antioxidants influence lung cancer risk. , 2003, Anticancer research.

[21]  Patrick M. Wright,et al.  Repair of oxidative DNA damage , 2007, Cell Biochemistry and Biophysics.

[22]  J. Yokota,et al.  Genetic polymorphisms and alternative splicing of the hOGG1 gene, that is involved in the repair of 8-hydroxyguanine in damaged DNA , 1998, Oncogene.

[23]  Nathaniel Rothman,et al.  Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. , 2004, Journal of the National Cancer Institute.

[24]  P Vineis,et al.  Markers of DNA repair and susceptibility to cancer in humans: an epidemiologic review. , 2000, Journal of the National Cancer Institute.

[25]  H. Dienemann,et al.  hOGG1 polymorphism and loss of heterozygosity (LOH): Significance for lung cancer susceptibility in a caucasian population , 2000, International journal of cancer.

[26]  A. Mander,et al.  Haplotype Analysis in Population-based Association Studies , 2001 .

[27]  山根 有人.  Suppressive activities of OGG1 and MYH proteins against G:C to T:A mutations caused by 8-hydroxyguanine but not by benzo[a]pyrene diol epoxide in human cells in vivo , 2004 .

[28]  D. Tang,et al.  DNA repair gene XRCC1 and XPD polymorphisms and risk of lung cancer in a Chinese population. , 2002, Carcinogenesis.

[29]  T. Lindahl,et al.  Quality control by DNA repair. , 1999, Science.

[30]  J. Yokota,et al.  The OGG1 gene encodes a repair enzyme for oxidatively damaged DNA and is involved in human carcinogenesis. , 2001, Antioxidants & redox signaling.

[31]  P. Morin,et al.  High-throughput single nucleotide polymorphism genotyping by fluorescent 5' exonuclease assay. , 1999, BioTechniques.

[32]  F. Gilliland,et al.  The XRCC1 399 glutamine allele is a risk factor for adenocarcinoma of the lung. , 2001, Mutation research.

[33]  N. Risch,et al.  A comparison of linkage disequilibrium measures for fine-scale mapping. , 1995, Genomics.

[34]  B. Morris,et al.  hOGG1 Ser326Cys polymorphism and lung cancer susceptibility. , 1999, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[35]  F. Oesch,et al.  DNA repair activity of 8-oxoguanine DNA glycosylase 1 (OGG1) in human lymphocytes is not dependent on genetic polymorphism Ser326/Cys326. , 2001, Mutation research.

[36]  I. M. Jones,et al.  Challenges and complexities in estimating both the functional impact and the disease risk associated with the extensive genetic variation in human DNA repair genes. , 2003, Mutation research.

[37]  T. Lindahl.  Instability and decay of the primary structure of DNA , 1993, Nature.

[38]  A. Abbondandolo,et al.  Involvement of XRCC1 and DNA Ligase III Gene Products in DNA Base Excision Repair* , 1997, The Journal of Biological Chemistry.

[39]  Jacques Ferlay,et al.  Cancer incidence in five continents. , 1976, IARC scientific publications.

[40]  M. García-Closas,et al.  Misclassification in case-control studies of gene-environment interactions: assessment of bias and sample size. , 1999, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[41]  D. Kang,et al.  Gene-environment interactions between the smoking habit and polymorphisms in the DNA repair genes, APE1 Asp148Glu and XRCC1 Arg399Gln, in Japanese lung cancer risk. , 2004, Carcinogenesis.

[42]  M. Dizdaroglu,et al.  Excision of oxidatively damaged DNA bases by the human alpha-hOgg1 protein and the polymorphic alpha-hOgg1(Ser326Cys) protein which is frequently found in human populations. , 1999, Nucleic acids research.

[43]  C. Ulrich,et al.  Polymorphisms in DNA repair genes and associations with cancer risk. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[44]  T. Mccaffrey,et al.  The human OGG1 DNA repair enzyme and its association with orolaryngeal cancer risk. , 2002, Carcinogenesis.

[45]  M. Spitz,et al.  From genotype to phenotype: correlating XRCC1 polymorphisms with mutagen sensitivity. , 2003, DNA repair.

[46]  D. Hamer,et al.  High-throughput SNP genotyping by allele-specific PCR with universal energy-transfer-labeled primers. , 2001, Genome research.

[47]  J. Hall,et al.  8-Hydroxydeoxyguanosine in DNA from leukocytes of healthy adults: relationship with cigarette smoking, environmental tobacco smoke, alcohol and coffee consumption. , 1999, Mutation research.

[48]  A. Tomkinson,et al.  Requirement for human AP endonuclease 1 for repair of 3'-blocking damage at DNA single-strand breaks induced by reactive oxygen species. , 2000, Carcinogenesis.

[49]  F. Skorpen,et al.  Base excision repair of DNA in mammalian cells , 2000, FEBS letters.

[50]  C. H. Kim,et al.  Polymorphism of the DNA repair gene XRCC1 and risk of primary lung cancer. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[51]  M. Thun,et al.  Tobacco smoke and involuntary smoking. , 2004, IARC monographs on the evaluation of carcinogenic risks to humans.

[52]  G. Haenen,et al.  A multi-biomarker approach to study the effects of smoking on oxidative DNA damage and repair and antioxidative defense mechanisms. , 2001, Carcinogenesis.

[53]  D. Albanes,et al.  Polymorphisms in the DNA repair genes XPD, XRCC1, XRCC3, and APE/ref-1, and the risk of lung cancer among male smokers in Finland. , 2003, Cancer letters.

[54]  Jinshui Fan,et al.  XRCC1 co-localizes and physically interacts with PCNA. , 2004, Nucleic acids research.

[55]  J. Radicella,et al.  Characterization of the hOGG1 promoter and its expression during the cell cycle. , 2000, Mutation research.

[56]  H. Norppa,et al.  Genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes: role in mutagen sensitivity. , 2002, Carcinogenesis.