TERT Promoter Mutation C228T Increases Risk for Tumor Recurrence and Death in Head and Neck Cancer Patients.

Lidia Maria Rebolho Batista Arantes,Ana Carolina De Carvalho,Bruna Pereira Sorroche,Rui Manuel Reis,Adriana Cruvinel-Carloni,Cristovam Scapulatempo-Neto,André Lopes Carvalho

doi:10.3389/fonc.2020.01275

Abstract

Background: Head and neck squamous cell carcinoma (HNSCC) is usually associated to tobacco and alcohol consumption. Increased telomerase activity has been consistently detected in 80–90% of malignant tumors, including HNSCC. Mutations within the promoter region of telomerase reverse transcriptase (TERT) that confer enhanced TERT promoter activity have been reported in two major hotspots, designated C228T and C250T.Objectives: To evaluate TERT promoter mutations C228T and C250T in HNSCC patients from Brazil and correlate with patients' outcome.Materials and Methods: Formalin-fixed paraffin-embedded tissues were obtained from 88 HNSCC patients and analyzed for TERT promoter mutations C228T and C250T by pyrosequencing.Results: The overall prevalence of hotspot TERT mutations in HNSCC samples was of 27.3%, with 6.8% at locus C228T and 20.5% at C250T. The majority (92%) of mutated cases were located in oral cavity, mainly at the tongue. We observed that 94.4% of the patients harboring TERT promoter mutation C250T were alcohol consumers (p = 0.032) and 66.7% of the patients harboring TERT promoter mutation C228T were not alcohol consumers (p = 0.035). The presence of C228T mutation impacted patient outcome, with a significant decrease in disease-free survival (20.0 vs. 63.0%, p =0.017) and in overall survival (16.7 vs. 45.1%, p = 0.017).Conclusion: This is the first report of a TERT promoter mutations in HNSCC patients from South America. The high prevalence of TERT mutation, as well as its association with poor disease-free survival and overall survival, particular at C228T locus might serve as a prognostic biomarker in HNSCC to help clinicians in the management of treatment.

Highlights

834,860 new cases of head and neck cancer are diagnosed each year in the world that encompasses tumors of the oral cavity, pharynx, and larynx [1]
Tumor sites were subdivided into oral cavity (78.4%), larynx (12.5%), and pharynx (9.1%)
The results showed a frequency of 27.3% (24/88) telomerase reverse transcriptase (TERT) mutations in HNSCC, being 20.5% at C250T and 6.8% at C228T hotspot regions (Table 2)

Summary

Introduction

834,860 new cases of head and neck cancer are diagnosed each year in the world that encompasses tumors of the oral cavity, pharynx, and larynx [1]. The most common type is squamous cell carcinoma (HNSCC) which accounts for over 90% of all head and neck cancers [2]. Associated to tobacco and alcohol consumption [3], over the past decades, human papillomaviruses (HPV) have emerged as an important etiological factor for a subset of HNSCC from the oropharynx [4, 5]. Most HNSCC treatments are associated with high morbidity and toxicity, where recurrent and metastatic disease is usually incurable, highlighting the need for more effective therapies for these patients [7]. No new targeted therapies have been approved for HNSCC for decades, other than cetuximab in 2006, which affords only modest response rates (10–15%) as monotherapy [8, 9]. Head and neck squamous cell carcinoma (HNSCC) is usually associated to tobacco and alcohol consumption. Mutations within the promoter region of telomerase reverse transcriptase (TERT) that confer enhanced TERT promoter activity have been reported in two major hotspots, designated C228T and C250T

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Results

Conclusion