Association of tumor necrosis factor-alpha promoter variants with risk of HPV-associated oral squamous cell carcinoma

Abstract

BackgroundTumor necrosis factor alpha (TNF-α) plays an important role in inflammation, immunity, and defense against infection and clearance of human papillomavirus (HPV). Thus, genetic variants may modulate individual susceptibility to HPV-associated oral squamous cell carcinoma (OSCC).MethodsIn this study we genotyped four common single nucleotide polymorphisms (SNPs) in the TNF-α promoter [ −308G > A(rs1800629), -857C > T (rs1799724), -863C > A (rs1800630), and -1031T > C (rs1799964)] and determined HPV16 serology in 325 OSCC cases and 335 matched controls and tumor HPV status in 176 squamous cell carcinomas of the oropharynx (SCCOP) patients. Univariate and multivariable logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).ResultsWe found that HPV16 seropositivity alone was associated with an increased risk of OSCC (OR, 3.1; 95% CI, 2.1–4.6), and such risk of HPV16-associated OSCC was modified by each SNP. Patients with both HPV16 seropositivity and variant genotypes for each SNP had the highest risk when using patients with HPV16 seronegativity and a wild-type genotype as a comparison group. Moreover, similar results were observed for the combined risk genotypes of four variants and all such significant associations were more pronounced in several subgroups, particularly in SCCOP patients and never smokers. Notably, the combined risk genotypes of four variants were also significantly associated with tumor HPV-positive SCCOP.ConclusionTaken together, these results suggest that TNF-α SNPs may individually or, more likely, jointly affect individual susceptibility to HPV16-associated OSCC, particularly SCCOP and never smokers. Validation of our findings is warranted.

Genetic polymorphisms and HPV infection in oral squamous cell carcinomas

“…Polymorphisms in human IL-1b and TNF-a genes have also been reported to influence cytokine expression [54]. TNF-a can directly control HPV infection by induction of apoptosis in HPV-infected cells, such as cervical cancer cells [55 ]. The perturbation of the balance between proand anti-inflammatory cytokine levels can be caused by inherited gene mutations, from which common genetic variants can also alter the expression or function of key genes, disrupting the balance of cytokines, and thus affecting cancer risk and outcome.…”

Familial clustering of oropharyngeal squamous cell carcinoma in the Utah population

“…Supporting this are findings from multiple studies linking polymorphisms in immune mediators to an increased risk of cervical cancer . For HPV‐associated oropharyngeal cancer, polymorphisms in immune mediators, such as transforming growth factor‐beta1 and tumor necrosis factor‐alpha, as well as pathways critical to genome integrity and programmed cell death, such as p53 and p73, are linked to an increased risk of oropharyngeal cancer …”

Influence of functional polymorphisms in TNF-α, IL-8, and IL-10 cytokine genes on mRNA expression levels and risk of gastric cancer

“…Among the TNF-α-308 G/A and -857 C/T SNPs evaluated in this study, only TNF-α-857 C/T was found to be associated with gastric cancer. Several studies have reported the same association [9,20,[40][41][42][43], but studies attempting to associate cytokine expression with the presence of SNPs are uncommon [7].…”