University of North Carolina at Chapel Hill Graduate School
Doi
Abstract
Heavy drinking of alcoholic beverages increases risk of developing squamous cell carcinoma of the head and neck (SCCHN; oral, pharyngeal and laryngeal cancer). This study hypothesized that genetic variation in the ethanol metabolism and oxidative stress pathways may influence the occurrence of and survival from SCCHN. Interview and genotyping data were obtained from 1227 SCCHN cases and 1325 controls from the Carolina Head and Neck Cancer Epidemiology study, a population-based case-control study of head and neck cancer conducted in North Carolina from 2002-2006. Vital status through 2008 was obtained from the National Death Index. A panel of 45 single nucleotide polymorphisms (SNPs) in the ethanol and 19 SNPs in the oxidative stress metabolism pathways were evaluated in relation to the risk of SCCHN using logistic regression and in relation to all-cause and cancer-specific survival using Cox regression. Bonferroni- corrected p-values were also estimated. Two SNPs were associated with SCCHN risk: ADH1B rs1229984 A allele [odds ratio (OR)=0.7, 95% confidence interval (CI)=0.6-0.9)] and ALDH2 rs2238151 C allele (OR=1.2, 95% CI=1.1-1.4). Three SNPs were associated with cancer risk in anatomic sub-sites: ADH1B rs17028834 C allele (larynx, OR=1.5, 95% CI=1.1-2.0), SOD2 rs4342445 A allele (oral cavity, OR=1.3, 95% CI=1.1-1.6), and SOD2 rs5746134 T allele (hypopharynx, OR=2.1, 95% CI=1.2-3.7). Four SNPs in alcohol metabolism genes interacted with level of alcohol consumption: ALDH2 rs2238151, ADH1B rs1159918, ADH7 rs1154460, and CYP2E1 rs2249695. No interactions with alcohol were found for oxidative stress pathway SNPs. Minor alleles of two SNPs in CYP2E1 - the C allele of both rs3813865 and rs8192772 - were associated with increased hazard of cancer-specific death [hazard ratio (HR)=2.09, 95%CI=1.38-3.18; HR=1.71, 95% CI=1.23-2.37, respectively]. No associations with survival were found for SNPs in ADH1B, ADH1C, ADH4, ADH7, ALDH2, GPx2, GPx4, and CAT. Previously unreported associations of SNPs in ALDH2, CYP2E1, GPX2, SOD1, and SOD2 with tumor incidence, and in CYP2E1 with cancer-specific survival, warrant further investigation. Associations with cancer incidence provide evidence that genetic variation in alcohol and oxidative stress pathways influence SCCHN carcinogenesis.Doctor of Philosoph
