Evaluation of germline and tumor DNA methylome in patients with pheochromocytoma and paraganglioma with SDHB germline pathogenic variants.

• Grant number: 25/00196-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: July 01, 2025
• End date: June 30, 2028
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Madson Queiroz Almeida
• Grantee: Eduardo Cunha Lobato
• 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) or from sympathetic/parasympathetic ganglia (paragangliomas). These tumors are one of the most inheritable forms of neoplasia, with 30-35% of PPGLs harboring germline pathogenic or likely pathogenic variants (PVs). In the Brazilian population, this proportion is even larger, since approximately 48% of cases harbor germline PVs in known susceptibility genes. Among these genes, it is important to highlight the PVs in the succinate dehydrogenase complex iron sulfur subunit B (SDHB) gene, which, besides having a more aggressive behavior and a characteristic tumoral epigenetic pattern, is the most prevalent germline PV site in Brazilian PPGLs. In 15-20% of pheochromocytomas and in 30-40% of paragangliomas, metastatic disease is present, characterized by the presence of tumors in non-chromaffin tissues. Factors such as extra-adrenal location, size, noradrenergic secretion, and germline PVs in genes of the cellular hypoxia pathway can increase the risk of metastases. However, all PPGLs are considered potentially metastatic, as there is currently no knowledge of markers for the definitive distinction of a PPGL with metastatic risk. Even in the case of PVs in high-risk genes (such as SDHB), the occurrence of metastasis does not happen in all patients, with the definitive reason behind this difference remaining unknown. Hence, the search for new prognosis markers is fundamental for the personalized management of each case. Epigenetic mechanisms, such as DNA methylation, have been target of growing attention in the study of PPGLs, since these tumors present distinct tumor methylation profiles according to the mutated gene. However, to date, no study has investigated the global DNA methylome in peripheral blood from patients with PPGLs to identify prognostic markers for metastasis. Our hypothesis is that the analysis of global DNA methylome in peripheral blood, combined with tumor methylation and the spectrum of germline PVs will contribute to identifying epigenetic DNA methylation signatures associated with tumor recurrence and metastatic disease. To achieve this goal, we will conduct a global DNA methylome analysis in blood from a cohort of 31 index patients with SDHB pathogenic variants (paired with tumor samples), including 15 metastatic and 16 non-metastatic cases. Additionally, the global methylome data will be integrated with genetic diagnosis and tumor gene expression through tumor RNA sequencing. (AU)