Genetic investigation of aldosterone-producing adrenocortical tumors by next generation sequencing

• Grant number: 15/17049-8
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2016
• End date: June 30, 2018
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Madson Queiroz Almeida
• Grantee: Madson Queiroz Almeida
• Host Institution: Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Arterial hypertension (AH) is a major cardiovascular risk factor that affects 10% to 40% of the adult population in industrialized countries. Primary aldosteronism (PA) is the most common form of secondary hypertension with an estimated prevalence of approximately 10% in referred patients. In the last 5 years, considerable advances toward understanding of molecular genetics of aldosterone-producing tumors (aldosteronomas) have been made through the identification of mutations in ion-selective channels that regulate membrane potential. Somatic mutations in KCNJ5 gene, encoding the GIRK4 K+ channel, were identified in 38% of aldosteronomas. More recently, somatic mutations in ATP1A1 gene, encoding a ±1 subunit of Na+,K+-ATPase channel, and in the ATP2B3 gene, endoding a Ca+2-ATPase channel, were found in 5,3% and 1,7% of aldosteronomas, respectively. Additionally, mutations in CACNA1D gene, encoding a Ca+2 voltage-dependent channel, were demonstrated in 9,3% of aldosteronomas. Then, driven mutations were not identified in approximately 46% of aldosteronomas. The aims of our study are: 1) to investigate somatic mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D genes in a Brazilian cohort of aldosteronomas; 2) To perform exome sequencing of negative aldosteronomas for KCNJ5, ATP1A1, ATP2B3 and CACNA1D mutations; 3) To correlate molecular findings with clinical patient data; 4) To validate the novel genetic variants by automated sequencing. To achieve these goals, we will employ the following tools: real-time quantitative PCR, automated SANGER sequencing and next-generation sequencing with bioinformatic analysis. We expect that this project will better characterize the spectrum of somatic mutations of Brazilian aldosteronomas and identify new genes involved with the pathogenesis of these tumors. (AU)

Scientific publications

(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.; PETENUCI, JANAINA; LOURENCO JR, DELMAR M.; TRARBACH, ERICKA B.; PEREIRA, MARIA ADELAIDE A.; CORREA D'EUR, JOYA EMILIE; HOFF, ANA O.; LERARIO, ANTONIO M.; ZERBINI, MARIA CLAUDIA N.; SIQUEIRA, SHEILA; et al. New Insights Into Pheochromocytoma Surveillance of Young Patients With VHL Missense Mutations. JOURNAL OF THE ENDOCRINE SOCIETY, v. 3, n. 9, p. 1682-1692, SEP 2019. (15/17049-8)

VILELA, LETICIA A. P.; RASSI-CRUZ, MARCELA; GUIMARAES, AUGUSTO G.; MOISES, CAIO C. S.; FREITAS, THAIS C.; ALENCAR, NATALIA P.; PETENUCI, JANAINA; GOLDBAUM, TATIANA S.; MACIEL, ANA ALICE W.; PEREIRA, MARIA ADELAIDE A.; et al. KCNJ5 Somatic Mutation Is a Predictor of Hypertension Remission After Adrenalectomy for Unilateral Primary Aldosteronism. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, v. 104, n. 10, p. 4695-4702, OCT 2019. (15/17049-8)

RASSI-CRUZ, MARCELA; MARIA, ANDREA G.; FAUCZ, FABIO R.; LONDON, EDRA; VILELA, LETICIA A. P.; SANTANA, LUCAS S.; BENEDETTI, ANNA FLAVIA F.; GOLDBAUM, TATIANA S.; TANNO, FABIO Y.; SROUGI, VITOR; et al. Phosphodiesterase 2A and 3B variants are associated with primary aldosteronism. Endocrine-Related Cancer, v. 28, n. 1, p. 1-13, JAN 2021. (17/13394-8, 18/23470-6, 15/17049-8)