Investigation of Somatic Pathogenic Variants in the Telomerase Reverse Transcriptase (TERT) Gene Promoter in Pheochromocytomas and Paragangliomas

• Grant number: 24/16730-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2024
• End date: October 31, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Madson Queiroz Almeida
• Grantee: Lucas Batini Araujo
• Host Institution: Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 19/15873-6 - Investigation of new genetic, clinical and pathological aspects of endocrine arterial hypertension, AP.TEM

Abstract

Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from chromaffin cells of the adrenal medulla (pheochromocytomas, representing 80% of cases) or from the thoracic and abdominal paravertebral sympathetic ganglia, or from the head and neck parasympathetic ganglia (paragangliomas, accounting for 20% of cases). PPGLs are caused by germline pathogenic or likely pathogenic variants (PVs) in 30% of cases, but this frequency of hereditary cases reaches 48% in Brazil. Approximately 15%-20% of PPGLs are metastatic, defined by the presence of tumors in non-chromaffin tissues. Although certain characteristics (such as extra-adrenal location, size, and noradrenergic biochemical profile, and germline PVs in hypoxia-related genes) increase the risk of metastasis, all PPGLs have metastatic potential. Therefore, identifying new prognostic markers is essential for personalized management of these patients. Increased expression of the Telomerase Reverse Transcriptase (TERT) gene corresponds to the main mechanism of replicative immortalization and metastasis. PVs in the TERT gene promoter are associated with metastatic disease in PPGLs. The aim of this study is to investigate somatic PVs in the TERT promoter region in our cohort of PPGLs and correlate them with the development of metastatic disease. To this task, we will sequence the TERT promoter by automatic SANGER sequencing in a cohort of 90 patients with PPGLs (60 non-metastatic and 30 metastatic). We hope that our results will consolidate another molecular marker that will be useful in clinical practice.