Carcinogenesis Advance Access originally published online on July 16, 2008
Carcinogenesis 2008 29(8):1560-1566; doi:10.1093/carcin/bgn089
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Genotypes and haplotypes of ERCC1 and ERCC2/XPD genes predict levels of benzo[a]pyrene diol epoxide-induced DNA adducts in cultured primary lymphocytes from healthy individuals: a genotype–phenotype correlation analysis
1 Department of Epidemiology
2 Department of Gastrointestinal Medical Oncology
3 Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
* To whom correspondence should be addressed. Tel: +1 713 792 3020; Fax: +1 713 563 0999; Email: qwei{at}mdanderson.org.
Benzo[a]pyrene diol epoxide (BPDE)-induced DNA adducts are a risk factor for tobacco-related cancers. Excision repair cross-complementing complementation group 1 (ERCC1) and excision repair cross-complementing complementation group 2/xeroderma pigmentosum D (ERCC2/XPD) participate in the nucleotide excision repair (NER) pathway that removes BPDE–DNA adducts; however, few studies have provided population-based evidence for this association. Therefore, we assayed for levels of in vitro BPDE-induced DNA adducts and genotypes of single-nucleotide polymorphisms (SNPs) of the NER genes ERCC1 (rs3212986 and rs11615) and ERCC2/XPD (rs13181, rs1799793 and rs238406) in 707 healthy non-Hispanic whites. The linear trend test of increased adduct values in never to former to current smokers was statistically significant (Ptrend = 0.0107). The median DNA adduct levels for the ERCC2 rs1799793 GG, GA and AA genotypes were 23, 29 and 30, respectively (Ptrend = 0.057), but this trend was not observed for other SNPs. After adjustment for covariates, adduct values larger than the median value were significantly associated with the genotypes ERCC1 rs3212986TT [odds ratio (OR) = 1.89, 95% confidence interval (CI) = 1.03–3.48] and ERCC2/XPD rs238406AA (OR = 0.64, 95% CI = 0.41–0.99) and rs238406CA (OR = 0.63, 95% CI = 0.45–0.89) compared with their corresponding wild-type homozygous genotypes. The results of haplotype analysis further suggested that haplotypes CAC and CGA of ERCC2/XPD, TC of ERCC1 and CACTC of ERCC2/XPD and ERCC1 were significantly associated with high levels of DNA adducts compared with their most common haplotypes. Our findings suggest that the genotypes and haplotypes of ERCC1 and ERCC2/XPD may have an effect on in vitro BPDE-induced DNA adduct levels.
Abbreviations: BPDE, benzo[a]pyrene diol epoxide; CI, confidence interval; ERCC1, excision repair cross-complementing complementation group 1; ERCC2, excision repair cross-complementing complementation group 2; FPRP, false-positive report probability; NER, nucleotide excision repair; OR, odds ratio; RAL, relative adduct labeling; SNP, single-nucleotide polymorphism; XPD, xeroderma pigmentosum D
Received December 27, 2007; revised March 12, 2008; accepted March 19, 2008.
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