title: Polymorphisms in ERCC1 and ERCC2/XPD genes and carcinogen DNA adducts in human lung.
abstract: OBJECTIVE
  In this exploratory study, we aimed to investigate whether polymorphisms in excision repair cross-complementing group 1 (ERCC1) and excision repair cross-complementing group 2/xeroderma pigmentosum group D (ERCC2/XPD) in the nucleotide excision repair (NER) pathways associated with DNA adducts in human lung tissue. We also analyzed the association stratified by the major histologic subtypes of non-small cell lung cancer (NSCLC): adenocarcinoma (ADC) and squamous cell carcinoma (SQCC).
  
  
  METHODS
  The study population consisted of 107 early stage NSCLC patients from the Massachusetts General Hospital (MGH) in Boston who underwent curative surgical resection. Genotyping was completed for SNPs in ERCC1 [C8092A (rs3212986) and C118T (rs11615)] and ERCC2/XPD [Asp312Asn (rs1799793) and Lys751Gln (rs1052559)] using a PCR-RFLP method and the PCR with fluorescent allele-specific oligonucleotide probes (Taqman). DNA adduct levels were measured as relative adduct levels per 10(10) nucleotides by (32)P-postlabeling in non-tumor lung tissue.
  
  
  RESULTS
  After adjusting for potential confounders, lung DNA adduct levels increased by 103.2% [95% confidence interval (CI), -11.5 to 366.6] for ERCC2/XPD rs1799793AA genotype compared with their corresponding wild type homozygous genotypes in overall NSCLC, but the difference did not reach statistical significance. When we stratified by the subtypes of NSCLC, we found that DNA adducts levels in lung increased by 204.9% (95% CI, 0.8 to 822.2, P=0.059) for ERCC2/XPD rs1799793AA genotype in subjects with SQCC and the trend was statistically significant (P for trend=0.0489).
  
  
  CONCLUSIONS
  Polymorphisms in ERCC2/XPD Asp312Asn may be associated with increased DNA adduct levels in the lung, especially among subjects with SQCC. Further large scale studies are needed to confirm our findings.
authors.affiliation: Environmental and Occupational Medicine and Epidemiology Program, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Institute of Environmental Health, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: Chen-yu
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Environmental and Occupational Medicine and Epidemiology Program, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.affiliation: Environmental and Occupational Medicine and Epidemiology Program, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: dchris@hsph.harvard.edu.
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000235:genetics*; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000235:genetics*; D018736:DNA Adducts / Q000032:analysis* / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000737:chemistry / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*
chemical_list: D018736:DNA Adducts; D004268:DNA-Binding Proteins; C071447:ERCC1 protein, human; D004720:Endonucleases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human
keywords: DNA adduct; DNA repair; ERCC1; ERCC2/XPD; Non-small cell lung cancer