Gene-environment interactions of novel variants associated with head and neck cancer

Abstract

Background: A genome-wide association study for upper aerodigestive tract cancers identified 19 candidate single-nucleotide polymorphisms (SNPs). We used these SNPs to investigate the potential gene-gene and gene-environment interactions in head and neck squamous cell carcinoma (HNSCC) risk.

Methods: The 19 variants were genotyped using Taqman assays among 575 cases and 676 controls in our population-based case-control study.

Results: A restricted cubic spline model suggested both ADH1B and HEL308 modified the association between smoking pack-years and HNSCC. Classification and regression tree analysis demonstrated a higher-order interaction 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 the highest risk of HNSCC (odds ratio = 1.84).

Conclusions: Our results suggest that the risk associated with these variants may be specifically important among specific exposure groups.

Figure 1. The association between alcohol consumption and head and neck squamous cell carcinoma (HNSCC) stratified by HEL308 genotypes

This figure shows the dose-response relationship between alcohol use and HNSCC stratified by HEL308 genotypes (C/C+C/T and T/T). The plot was truncated at 80 drinks per week because few consumers drink greater than that amount. Subjects with T/T genotypes tended to have a lower risk relative to those carrying C/C+C/T genotypes with the same amount of alcohol consumption. A cross between the intervals for the two genotypes was oberved. Likelihood ratio test did not suggest a significant departure from multiplicative interaction.

Figure 2. The association between smoking and HNSCC stratified by HEL308 genotypes

This figure displays the trend of HNSCC risk with the increase of smoking pack years separated by HEL308 genotypes (C/C+C/T and T/T). The plot was truncated at 100 pack years due to the small number of subjects smoking beyond that amount. A marked deviation between the two genotypes was observed beyond 70 smoking pack years. A likelihood ratio test for multiplicative interaction between smoking pack-years and HEL308 genotypes suggested significance (P interaction=0.026).

Figure 3. The association between smoking and HNSCC stratified by ADH1B genotypes

This figure presents the dose-response relationship between smoking and HNSCC risk stratified by ADH1B genotypes (C/C and T/C). The risk of HNSCC increased with increasing smoking pack years among those with ADH1B homozygous wild-type genotype (C/C), whereas a flat trend of HNSCC risk was observed for those with ADH1B heterozygous genotype (T/C). Here, the likelihood ratio test for multiplicative interaction between smoking pack years and ADH1B genotypes suggested a significant departure from multiplicative interaction (P interaction=0.0016).

Figure 4. Classification and regression tree (CART) analysis of genetic polymorphisms and smoking status

This figure displays the tree structure generated using CART analysis. Smoking status was the initial split, and ADH1B subsequently separated the ever smokers into two subgroups (C/C and T/C+T/C). Subsequent splits were FLJ13089 and FLJ35784. The final tree structure contained 5 terminal nodes, representing a range of low- versus high-risk subgroups as defined by the different combination of smoking status and genotypes. Smokers carrying ADH1B wild-type (C/C) and FLJ13089 A/G+A/A genotypes had a highest risk of HNSCC (OR=1.84). The combination of ADH1B wild-type, FLJ13089 G/G and FLJ35784 any genotypes had an attenuated positive association with HNSCC.