Single nucleotide polymorphisms in nucleotide excision repair genes and head and neck cancer risk and outcomes

An estimated 52,140 incident head and neck cancers (HNC), with 11,460 associated deaths occurred in the US during 2011. Cigarette smoke contributes to HNC risk by causing bulky DNA adducts. Such adducts are removed by nucleotide excision repair (NER) processes. Previous studies have suggested that polymorphisms in NER genes are independent risk factors for HNC, as well as modifiers of smoking-HNC associations. Treatment of HNC with radiation and platinum-based chemotherapies also produce bulky DNA adducts, and previous studies suggest independent NER SNP and joint SNP-treatment associations with HNC survival. Race-specific (white and African American) odds ratios (ORs) and 95% intervals (Is) for the individual and joint effects of 84 single nucleotide polymorphisms (SNPs) in 15 NER genes and cigarette smoking on HNC risk were estimated from unconditional and hierarchical logistic regression models using data from the Carolina Head and Neck Cancer Epidemiology (CHANCE) Study (1,227 cases and 1,325 controls). Race-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for the individual and joint effects of the same SNPs in NER genes and treatment (surgery, radiation, and chemotherapy) on survival among cases were estimated using Cox proportional hazards models, with Bonferroni corrected p-values to account for multiple comparisons. Among whites, rs4150403 on ERCC3 (XPB) was associated with increased HNC risk (OR=1.28, 95% I=1.01, 1.61). Among African Americans, rs4253132 on ERCC6 was associated with decreased HNC risk (OR=0.62, 95% I=0.45, 0.86). For HNC survival, no associations were significant at a Bonferroni-corrected alpha of 0.0006. However, rs3136038 and rs3136130 of ERCC4 and rs50871 of ERCC2 (XPD) were suggestively associated with similarly improved survival among whites at an uncorrected 0.05 alpha (overall survival HRs∼0.80 and disease-specific survival HRs∼0.70). Likewise, rs2607755 of XPC was suggestively associated with improved survival among African Americans (overall survival HR=0.62 and disease-specific survival HR=0.51). A few SNP-cigarette smoking and SNP-treatment interactions suggested possible additive effects. We conducted one of the largest and most comprehensive evaluations of SNPs in multiple NER genes, identifying only a few SNPs from biologically plausible genes associated with HNC risk or survival, and possibly interacting with cigarette smoking or treatment.Doctor of Philosoph