Interaction between tumour necrosis factor-α gene polymorphisms and substance use on risk of betel quid-related oral and pharyngeal squamous cell carcinoma in Taiwan

Objective: Betel quid (BQ) components induce the secretion of tumour necrosis factor-alpha (TNF-alpha) in oral keratinocytes, which promotes oral mucosal inflammation and oral cancer. This study was carried out to evaluate the association of TNFA genetic variants (-308G>A and -238G>A) with the risk and prognosis of BQ-related oral and pharyngeal squamous cell carcinoma (OPSCC). Design: A total of 403 subjects (205 cancer cases and 198 healthy controls) who habitually chewed BQ were recruited. The genotypes were determined by TaqMan real-time assays. Results: G allele and G/G genotype at TNFA -308 were associated with a 1.95-fold (95%CI: 1.16-3.28, p(corrected) = 0.024) and 2.28-fold (95%CI: 1.30-4.00, P-corrected = 0.008) increased risk of cancer as compared to those with A allele or A/A + A/G genotypes, respectively. In addition, G allele (p = 0.080) and G/G genotype (p = 0.076) at TNFA -238 were associated with a borderline but statistically significant increased risk of OPSCC. The combined GIG + G/G genotype at both loci had a 2.37-fold increased risk of OPSCC as compared to those with other combined genotypes (95%CI: 1.41-4.00, p = 0.001). Interactions between combined genotypes and smoking status were also found to contribute to risk of BQ-related OPSCC. There was no association of TNFA genotypes with clinicopathologic findings or the survival of OPSCC patients. Conclusions: BQ-chewers who carry the G allele or G/G genotype in TNFA -308 may have an increased risk of OPSCC. The intensity of cigarette smoking modulates the effect of the combined TNFA genotypes on risk of BQ-related OPSCC. Crown Copyright (C) 2011 Published by Elsevier Ltd. All rights reserved.