ASSOCIATION OF A GENETIC VARIANT IN THE SEROTONIN MODULATOR WITH RISK AND PROGNOSIS OF OROPHARYNX CANCER PATIENTS

Background:In addition to the regulation of emotions, serotonin (5-HT) is also responsible for the activation of pathways associated with cell proliferation. The synthesis of 5-HT is dependent on family enzymes tryptophan-hydroxylase (TPH). 5-HT can influence the progression of tumors through the activation of the phosphatidylinositol 3-kinase (PI3K) and serine-threonine kinase (AKT) pathways, related to cell proliferation, migration and differentiation. Polymorphisms in genes involved in biosynthesis and 5-HT uptake have been reported, suggesting that genetic variability may be related to tumor development. The genetic single nucleotide variation (SNV) located in the promoter region of the TPH2 (rs4570625, c.-844G > T) gene can modulate 5-HT synthesis. However, the effects of referred SNV on the risk of occurrence and prognosis of oropharynx squamous cell carcinoma (OPSCC) have not yet been described. Objectives: Evaluate the influence of SNV TPH2 rs4570625 on the risk and prognosis of OPSCC. Methods: TPH2 genotypes of 210 OPSCC patients (median age: 57 years, 191 men, 19 women, 199 smokers, 11 non-smokers) and 210 controls (median age: 43 years, 161 men, 49 women, 183 smokers, 27 non-smokers) were identified in DNA by real-time PCR using TaqMan^® assays. Patients were treated with conventional protocols, based in cisplatin and radiotherapy. The differences between groups were assessed by chi-square and multiple logistic regression. Event-free survival (EFS) and overall survival (OS) times were estimated by Kaplan-Meier (K-M) and Cox methods. Results: The frequencies of GT or TT (48.6% vs. 47.1%, p = 0.65) and TT (6.7% vs. 7.6%, p = 0.88) genotypes were similar in patients and controls. Individuals with referred genotypes were under similar risks of OPSCC. At 60 months, EFS was similar in patients with TPH2 genotypes (GG: 50.9%, GT: 51.3%, and TT: 58.9%, p = 0.64, K-M estimates). However, the OS was shorter in patients with GG or GT genotypes than those with variant GG genotype (45.0% vs. 62.5%, p = 0.02, K-M estimates; Cox: hazard ratio: 2.76, 95% confidence interval: 1.10-6.90, p = 0.03). Conclusions: Our results suggest, for the first time, that TPH2 rs4570625 SNV is an important inherited factor for the prognosis of OPSCC. Our findings, once validated in additional studies, will contribute to personalize the therapy of OPSCC patients.