Whole exome sequencing for the investigation of novel genetic causes of metastatic Pheochromocytomas and Paragangliomas

• Grant number: 21/11240-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2021
• End date: October 31, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Madson Queiroz Almeida
• Grantee: Felipe Freitas de Castro
• 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 are neuroendocrine tumors derived from chromaffin cells. Approximately 15-20% of Pheochromocytomas and Paragangliomas are classified as metastatic, defined by the presence of tumor in non-chromaffin tissues. To date, at least 20 susceptibility genes for PPGLs have been reported. Germline pathogenic variants in SDHB gene are the most well-established risk factor to predict metastatic disease in 40-50% of cases. In our Institution, germline genetic alterations in SDHB were found in 25% of the cases, SDHD 3%, NF1 3%, SDHA 3% and MET 3%. Therefore, 63% of the metastatic Pheochromocytomas and Paragangliomas of our cohort remain without genetic diagnosis after investigation using a gene target sequencing panel by massive parallel sequencing. The aim of this project is to investigate novel genetic causes of metastatic Pheochromocytomas and Paragangliomas. The specific aims are: 1) to perform whole exome sequencing of germline and tumor DNA of 20 patients with metastatic pheochromocytoma or paraganglioma; 2) to correlate the genetic findings with clinical and follow-up data; 3) to perform functional studies to evaluate the pathogenicity of the rare and in silico deleterious germline variants in new candidate genes. (AU)

Scientific publications

(7)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

FAGUNDES, GUSTAVO F. C.; FREITAS-CASTRO, FELIPE; SANTANA, LUCAS S.; AFONSO, ANA CAROLINE F.; PETENUCI, JANAINA; FUNARI, MARIANA F. A.; GUIMARAES, AUGUSTO G.; LEDESMA, FELIPE L.; PEREIRA, MARIA ADELAIDE A.; VICTOR, CAROLINA R.; et al. Evidence for a Founder Effect of SDHB Exon 1 Deletion in Brazilian Patients With Paraganglioma. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, v. N/A, p. 10-pg., 2023-01-18. (19/15873-6, 21/10101-5, 21/11240-9, 21/10363-0)

FREITAS-CASTRO, FELIPE; ALMEIDA, MADSON Q.. Personalized management for phaeochromocytomas and paragangliomas in Latin America: A genetic perspective. BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM, v. 39, n. 1, p. 8-pg., 2025-01-01. (19/15873-6, 21/11240-9)

MACIEL, ANA ALICE W.; DANILOVIC, DEBORA L. S.; SOARES, IBERE C.; FREITAS, THAIS C.; OKUBO, JESSICA; FAGUNDES, GUSTAVO F. C.; FREITAS-CASTRO, FELIPE; SANTANA, LUCAS S.; GUIMARAES, AUGUSTO G.; CALSAVARA, VINICIUS F.; et al. Association Between Papillary Thyroid Cancer and Primary Aldosteronism in Individuals With Hypertension. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, v. N/A, p. 12-pg., 2024-09-30. (21/10101-5, 21/11240-9, 21/10363-0, 19/15873-6, 21/09879-1)

FREITAS, THAIS C.; MACIEL, ANA ALICE W.; FAGUNDES, GUSTAVO F. C.; PETENUCI, JANAINA; SANTANA, LUCAS S.; GUIMARAES, AUGUSTO G.; FREITAS-CASTRO, FELIPE; SROUGI, VICTOR; TANNO, FABIO Y.; CHAMBO, JOSE L.; et al. Efficacy of Oral Furosemide Test for Primary Aldosteronism Diagnosis. JOURNAL OF THE ENDOCRINE SOCIETY, v. 8, n. 1, p. 10-pg., 2023-12-01. (21/10101-5, 21/11240-9, 21/10363-0, 19/15873-6, 21/09879-1)

FREITAS-CASTRO, FELIPE; SANTANA, LUCAS S.; FAGUNDES, GUSTAVO F. C.; LOBATO, EDUARDO C.; AFONSO, ANA CAROLINE F.; NAKAMURA, IZABEL T.; LEDESMA, FELIPE L.; SOARES, IBERE C.; MENDONCA, BERENICE B.; LATRONICO, ANA CLAUDIA; et al. SLC25A11, a Novel Gene Associated With Carney-Stratakis Syndrome. JOURNAL OF THE ENDOCRINE SOCIETY, v. 9, n. 5, p. 9-pg., 2025-05-01. (19/15873-6, 21/10363-0, 24/03610-9, 21/11240-9)

FAGUNDES, GUSTAVO F. C.; FREITAS-CASTRO, FELIPE; SANTANA, LUCAS S.; LEDESMA, FELIPE L.; PETENUCI, JANAINA; AFONSO, ANA CAROLINE F.; PEREIRA, CAIO A. A.; MACIEL, ANA ALICE W.; SOARES, IBERE C.; GOMES, NATHALIA L.; et al. Insights into the genetic landscape of pheochromocytomas and paragangliomas in a Brazilian cohort. EUROPEAN JOURNAL OF ENDOCRINOLOGY, v. 192, n. 1, p. 14-pg., 2025-01-06. (19/15873-6, 21/10363-0, 21/11240-9, 21/09879-1)

MORI, GUSTAVO H.; FAGUNDES, GUSTAVO F. C.; SANTANA, LUCAS S.; FREITAS-CASTRO, FELIPE; AFONSO, ANA CAROLINE F.; LOURENCO, DELMAR M.; PEREIRA, MARIA ADELAIDE A.; TANNO, FABIO Y.; SROUGI, VICTOR; CHAMBO, JOSE L.; et al. Pathogenicity of germline VHL variants is associated with renal cell carcinoma size in von Hippel-Lindau disease. ARCHIVES OF ENDOCRINOLOGY METABOLISM, v. 69, p. 6-pg., 2025-01-01. (19/15873-6, 21/10363-0, 21/11240-9)