Association studies of excision repair cross-complementation group 1 (ERCC1) haplotypes with lung and oral cancer risk in a Caucasian population Free

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A major cause of tobacco-induced cancer is the formation of bulky DNA adducts caused by various compounds such as the diol epoxide derivatives of polycyclic aromatic hydrocarbons. These DNA adducts are mutagenic if not repaired by the nucleotide excision repair (NER) system. A sub-optimal DNA repair capacity has been shown to be a risk factor for tobacco-induced lung and oral cancers. The human excision repair cross-complementation group 1 (ERCC1) gene encodes an NER protein that forms a heterodimer with nuclease XPF and links it to the core NER machinery. Since the ERCC1 protein is essential for a functional NER system, genetic variation in ERCC1 may contribute to impaired DNA repair capacity and increased lung and oral cancer risk. Previous association studies involving the ERCC1 gene focused primarily on two coding polymorphisms and yielded inconsistent results in different populations. In order to comprehensively capture common genetic variation in the ERCC1 gene, we used European ancestry data from the International HapMap project (CEPH samples) to assess linkage disequlibrium (LD) and choose tagSNPs in the ERCC1 gene and 10kb promoter region. Two blocks of high LD were identified. The first block contained four haplotypes in the coding region of the ERCC1 gene, which can be distinguished by three tagSNPs (rs3212948, rs3212955, rs735482), and the second block contained two haplotypes in the promoter region, which can be distinguished by one tagSNP (rs1319052). Pre-designed Taqman genotyping assays were used to determine the genotypes of these SNPs in 452 lung cancer cases, 174 oral cancer cases, and 790 healthy controls in a Caucasian population. Five-percent of samples were repeated for duplicate genotyping and there was 99.5% concordance of these quality controls with the original genotype call. All SNPs were found to be consistent with Hardy-Weinberg equilibrium. Haplotypes were estimated using expectation maximization (EM) algorithm and haplotype association with cancer was investigated using Haplo.stats software, adjusting for known covariates (age, gender, and pack-years). The genotype and haplotype frequencies matched previous estimates from CEPH Caucasians. There was no significant difference in the prevalence of individual SNPs when comparing lung and oral cancer cases with controls (p-values > 0.05). Similarly, there was no association between ERCC1haplotypes and lung or oral cancer susceptibility in this Caucasian population (p-values > 0.05). Lung cancer cases were also stratified by histology, sex, and smoking status in an attempt to identify any specific associations that might be present, but none were found. This study suggests that ERCC1 polymorphisms and haplotypes do not play a role in lung and oral cancer susceptibility in Caucasians.