Genetic variants in TNF-α promoter are predictors of recurrence in patients with squamous cell carcinoma of oropharynx after definitive radiotherapy

The promoter variants of TNF-α, a major regulator of immune and inflammation responses, have been implicated in cancer development and prognosis. Thus, we investigated associations between four TNF-α promoter variants and risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP). We evaluated associations of four TNF-α polymorphisms with risk of recurrence in a cohort of 846 patients with SCCOP. Log-rank test and multivariable Cox models were used to evaluate associations. Compared with patients with variant genotypes of the TNF-α -308 and TNF-α -863 polymorphisms, patients with common homozygous genotypes had worse disease-free survival (log-rank p = 0.0002 and p < 0.0001, respectively) and increased risk of SCCOP recurrence (HR, 1.9, 95% CI, 1.3-2.8 and HR, 1.9, 95% CI, 1.3-2.7, respectively) after multivariable adjustment. Furthermore, among patients with HPV16-positive tumors, those with common homozygous genotypes of the TNF-α -308 and -863 polymorphisms had worse disease-free survival (log-rank p = 0.005 and p = 0.007, respectively) and higher recurrence risk than patients with variant genotypes of these polymorphisms (HR, 5.1, 95% CI, 1.4-18.4 and HR, 3.7, 95% CI, 1.5-9.1, respectively), while no such significant associations were found for TNF-α -857 or -1031 polymorphisms. Our findings suggest that TNF-α -308 and -863 polymorphisms may modulate the risk of SCCOP recurrence in patients with HPV16-positive tumors. However, larger studies are needed to validate these results. What's new? Squamous cell carcinoma of the oropharynx (SCCOP) has been on the rise in the United States, despite declines in smoking rates. The immune regulator TNF-α is thought to play a critical role in defense against human papillomavirus (HPV) infection, to which the growing incidence of SCCOP has been attributed. Here, evaluation of four variants in TNF-α shows that common homozygous genotypes of TNF-α -308 and -863 polymorphisms are associated with an increased risk of SCCOP recurrence. The two polymorphisms may be potential biomarkers of genetic susceptibility to SCCOP recurrence in HPV-positive patients.