Functional Genetic Variants in TGFb1 and TGFbR1 in miRNA-Binding Sites Predict Outcomes in Patients with HPV-positive Oropharyngeal Squamous Cell Carcinoma

Purpose: TGF131 and TGF13 receptor 1 (TGF13R1) participate in regulation of the host's immune system and inflammatory responses and may serve as prognostic biomarkers for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC).Experimental Design: This study included 1,013 patients with incident OPSCC, of whom 489 had tumor HPV16 status deter-mined. All patients were genotyped for two functional polymorph-isms: TGFfi1 rs1800470 and TGFfiR1 rs334348. Univariate and multivariate Cox regression models were performed to evaluate associations between the polymorphisms and overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS).Results: Patients with TGFfi1 rs1800470 CT or CC genotype had 70%-80% reduced risks of OS, DSS, and DFS compared with patients with TT genotype, and patients with TGFfiR1 rs334348 GA or GG genotype had 30%-40% reduced risk of OS, DSS, and DFS compared with patients with AA genotype. Furthermore, among patients with HPV-positive (HPV thorn ) OPSCC, the same patterns were observed but the risk reductions were greater: up to 80%-90% for TGFfi1 rs1800470 CT or CC genotype and 70%-85% for TGFfiR1 rs334348 GA or GG genotype. The risk reductions were still greater (up to 17 to 25 times reduced) for patients with both TGFfi1 rs1800470 CT or CC genotype and TGFfiR1 rs334348 GA or GG genotype compared with patients with both TGFfi1 rs1800470 TT genotype and TGFfiR1 rs334348 AA genotype among patients with HPV thorn OPSCC.Conclusions: Our findings indicate that TGFfi1 rs1800470 and TGFfiR1 rs334348 may individually or jointly modify risks of death and recurrence in patients with OPSCC, particularly those with HPV thorn OPSCC undergoing definitive radiotherapy, and may serve as prognostic biomarkers, which could lead to better personalized treatment and improved prognosis.

Automated summary

This study found that TGFfi1 rs1800470 and TGFfiR1 rs334348 gene polymorphisms are associated with prognosis of HPV-associated oropharyngeal squamous cell carcinoma. These gene polymorphisms are related to overall survival, disease-specific survival, and disease-free survival in patients with OPSCC. The association is particularly significant in HPV-positive patients. These findings suggest that TGFfi1 rs1800470 and TGFfiR1 rs334348 may modify the risks of death and recurrence in OPSCC patients and can serve as prognostic biomarkers for better personalized treatment and improved prognosis.