<i>TGFβ1</i> Genetic Variants Predict Clinical Outcomes of HPV-Positive Oropharyngeal Cancer Patients after Definitive Radiotherapy.

Abstract

<b>Purpose:</b> TGFβ1 plays a critical role in inflammation and immune responses and treatment response and survival. <i>TGFβ1</i> variants may affect its expression level or functional efficiency, thus modifying tumor status and survival in human papillomavirus (HPV)-positive squamous cell carcinoma of the oropharynx (SCCOP).<b>Experimental Design:</b> We determined tumor HPV16 status and genotyped three <i>TGFβ1</i> polymorphisms in 564 incident SCCOP patients treated with radiotherapy or chemoradiation. Univariate and multivariable Cox models were used to evaluate the associations between the three polymorphisms and survival.<b>Results:</b> Overall, 85% of patients (482 of 564) had HPV16-positive SCCOP. We found that <i>TGFβ1</i> rs1982073 had statistically significant associations with survival, whereas <i>TGFβ1</i> rs1800469 and <i>TGFβ1</i> rs1800471 did not. Patients with <i>TGFβ1</i> rs1982073 CT/CC variant genotypes had significantly better overall, disease-specific, and disease-free survival compared with those with the corresponding common homozygous TT genotype (all log-rank: <i>P</i> < 0.001). Furthermore, these genotypes were significantly associated with an approximately 5 times reduced risk of overall death, death owing to disease, and recurrence after multivariable adjustment. Moreover, the stratified analyses by tumor HPV status indicated that the significant effects of <i>TGFβ1</i> rs1982073 polymorphism on survival were found among HPV16-positive SCCOP patients only. Finally, the functional relevance of these variants was further characterized.<b>Conclusions:</b> Our findings support that the <i>TGFβ1</i> rs1982073 polymorphism plays a significant role in the prognosis of SCCOP, especially in HPV16-positive SCCOP patients treated with chemoradiation. Prospective studies with larger sample sizes are needed to confirm these findings. <i>Clin Cancer Res; 24(9); 2225-33. ©2018 AACR</i>.