Single-Nucleotide Polymorphisms in Nucleotide Excision Repair Genes, Cigarette Smoking, and the Risk of Head and Neck Cancer

BACKGROUND: Cigarette smoking is associated with increased head and neck cancer (HNC) risk. Tobacco-related carcinogens are known to cause bulky DNA adducts. Nucleotide excision repair (NER) genes encode enzymes that remove adducts and may be independently associated with HNC, as well as modifiers of the association between smoking and HNC. METHODS: Using population-based case-control data from the Carolina Head and Neck Cancer Epidemiology (CHANCE) Study (1,227 cases and 1,325 controls), race-stratified (White, African American), conventional, and hierarchical logistic regression models were used to estimate ORs with 95% intervals (I) for the independent and joint effects of cigarette smoking and 84 single-nucleotide polymorphisms (SNP) from 15 NER genes on HNC risk. RESULTS: The odds of HNC were elevated among ever cigarette smokers and increased with smoking duration and frequency. Among Whites, rs4150403 on ERCC3 was associated with increased HNC odds (AA+AG vs. GG; OR, 1.28; 95% CI, 1.01-1.61). Among African Americans, rs4253132 on ERCC6 was associated with decreased HNC odds (CC+CT vs. TT; OR, 0.62; 95% CI, 0.45-0.86). Interactions between ever cigarette smoking and three SNPs (rs4253132 on ERCC6, rs2291120 on DDB2, and rs744154 on ERCC4) suggested possible departures from additivity among Whites. CONCLUSIONS: We did not find associations between some previously studied NER variants and HNC. We did identify new associations between two SNPs and HNC and three suggestive cigarette-SNP interactions to consider in future studies. IMPACT: We conducted one of the most comprehensive evaluations of NER variants, identifying a few SNPs from biologically plausible candidate genes associated with HNC and possibly interacting with cigarette smoking.