Abstract 3865: A post genome-wide association study: Gene and environment interaction in the risk of head and neck carcinoma

Abstract

Abstract A consortium of case-control studies of upper aerodigestive tract (UADT) cancers recently conducted a genome-wide association study (GWAS) and identified 20 candidate SNPs demonstrating significant independent risk for disease. Although this collaborative effort provided the sample size necessary to identify these candidates, it was not possible to investigate the interaction of these genes with environmental and demographic factors due to differences in the various participating studies’ designs, data collection strategies, and diseases examined. Thus, our study sought to investigate the potential low penetrance gene-gene and gene-environment interaction in head and neck squamous cell carcinoma (HNSCC) risk, we examined the significant variants identified from the initial GWAS and conducted a post-GWAS analysis of gene-environment and higher order gene-gene-environment interactions in our population-based case-control study of HNSCC. Cases were patients with incident HNSCC identified from nine medical facilities in Greater Boston, MA between December 1999 and December 2003. Controls were identified from Massachusetts town books using random selection and frequency-matched to cases on age (± 3 years), gender, and town of residence. There were twenty variants selected from initial GWAS for UADT cancers. These included 11 variants with p-values <10−5, 6 non-synonymous SNPs with p-values <10−4 and 2 variants with p-values <5×10−7 in restricting to UADT cancer subsite, or heavy drinkers/smokers. Finally, a non-synonmous SNP (rs1229984) was included. Taqman (Applied Biosystems) genotyping assays were designed and utilized to genotype the 575 cases and 676 controls. A restricted cubic spline model suggested both ADH1B and HEL308 modified the association between smoking pack-years and HNSCC. Subanalysis suggested the departure from multiplicative interaction between ADH1B and smoking was significant consistently across tumor sites (oral, pharynx and larynx). However, the departure from multiplicative interaction between HEL308 and smoking was only detected in oral cavity and pharyngeal sites. Classification and regression tree (CART) analysis demonstrated the higher order interactions between smoking status, ADH1B, FLJ13089 and FLJ35784 in HNSCC risk. Compared with ever smokers carrying ADH1B T/C+T/T genotypes, smokers carrying ADH1B C/C genotype and FLJ13089 A/G+A/A genotypes had a highest risk of HNSCC (OR=1.84; 95%CI: 0.98-3.47). Our study showed both ADH1B and HEL308 modified the association between smoking and HNSCC. Higher order interactions between smoking status, ADH1B, FLJ13089 and FLJ35784 in HNSCC risk were also observed. Together these results confirm and expand upon the associations observed in the initial GWAS and suggest that the risk associated with these variants may be specifically important amongst specific exposure groups. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3865.