Uncovering pathophysiological and molecular mechanisms involved in tumorigenesis by platforms for next-generation sequencing (NGS)

• Grant number: 14/03989-6
• Support Opportunities: Research Projects - Thematic Grants
• Duration: March 01, 2017 - February 29, 2024
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Margaret de Castro
• Grantee: Margaret de Castro
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Pesquisadores principais: Léa Maria Zanini Maciel ; Sonir Roberto Rauber Antonini
• Associated researchers: Ana Valeria Castro ; Ayrton Custodio Moreira ; Fabiano Pinto Saggioro ; Helio Rubens Machado ; Houtan Noushmehr ; Luciano Neder Serafini ; Paula Condé Lamparelli Elias ; Wilson Araújo da Silva Junior
• Associated grant(s): 22/15461-2 - Multi-user equipment approved in grant 2014/03989-6: SeqStudio Genetic Analyzer System, AP.EMU
• Associated scholarship(s): 22/09929-1 - GENERATION OF ANIMAL MODELS AND STUDY OF MOLECULAR MECHANISMS INVOLVED IN THE TUMORIGENESIS OF CORTICOTROPH TUMORS AND ADRENOCORTICAL CARCINOMAS, BP.PD; 22/04899-7 - Biochemical and molecular investigation of primary aldosteronism, BP.IC; 22/04883-3 - Identification of molecular variations involved in pituitary tumorigenesis based on exomic sequencing and transcriptome, BP.PD; + associated scholarships 21/04368-9 - Physiopathological and molecular mechanisms of tumorigenesis: Genomic scale sequencing platform based approach (NGS - Next-generation sequencing), BP.TT; 20/03835-0 - Application of standard Artificial Intelligence protocols on transcriptome of pediatric adrenocortical tumors for stratification and search for biomarkers, BP.TT; 19/08041-4 - Wnt/beta-catenin pathway in pediatric adrenocortical tumors, BP.IC; 19/00860-6 - Uncovering pathophysiological and molecular mechanisms involvedin tumorigenesis by platforms for next-generation sequencing (NGS), BP.PD; 19/00849-2 - Uncovering pathophysiological and molecular mechanisms involved in tumorigenesis by platforms for next-generation sequencing (NGS), BP.PD; 18/08210-8 - Next Generation Sequencing in Pediatric Adrenocortical Tumors, BP.PD - associated scholarships

Abstract

To elucidate the molecular pathogenesis of endocrine tumors, several studies have investigated the role of specific genes regulating the organ development, genes involved in tumorigenesis of other tissues, such as abnormalities in genes that lead to cycle progression and cell division (oncogenes) or genes that block the cell cycle (tumor suppressor genes), miRNAs, and large noncoding (lncRNAs). Significant advances have been observed in the molecular elucidation of various hereditary syndromes that occur with pituitary tumors [(McCune - Albright, Multiple endocrine neoplasia (MEN) type 1 and type 4, Carney's syndrome, and familial isolated pituitary adenoma (FIPA)]; with adrenal tumors (Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, Carney complex, McCune-Albright, MEN1); and with thyroid tumors (MEN2, Hereditary medullar thyroid carcinoma). All these advances occurred due approaches based on candidate genes and linkage studies, but the molecular pathogenesis of sporadic endocrine tumors has not been completely clarified. The new platforms of next generation sequencing (NGS) present major advantages for the analysis of 1) exoma (Target-seq analysis) 2) epigenomic (either by chromatin immunoprecipitation (ChIP) or promoter DNA methylation analysis), and 3) transcriptome. Therefore, this project aims to use NGS technology to better understand the process of central nervous system (glyomas) and endocrine tumorigenesis. Tumoral tissues will be obtained from patients followed in the Hospital das Clinicas, Faculty of Medicine of Ribeirão Preto, University of São Paulo (HCFMRP-USP). As controls, normal tissue samples will be obtained at CEMEL (Center of Forensic Medicine) from autopsies of patients with accidental or sudden death from cardiac causes. The NGS certainly will indicate new genes and/or new cell signaling pathways that may be keys of the enlightenment of endocrine tumorigenesis. (AU)

Scientific publications

(18)

(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)

BUENO, ANA CAROLINA; STECCHINI, MONICA F.; MARRERO-GUTIERREZ, JUNIER; MORE, CANDY BELLIDO; LEAL, LETICIA FERRO; GOMES, DEBORA CRISTIANE; DE LIMA NETO, DANIEL FERREIRA; BRANDALISE, SILVIA REGINA; CARDINALLI, IZILDA APARECIDA; YUNES, JOSE ANDRES; et al. Vitamin D receptor hypermethylation as a biomarker for pediatric adrenocortical tumors. EUROPEAN JOURNAL OF ENDOCRINOLOGY, v. 186, n. 5, p. 13-pg., 2022-05-01. (15/19663-5, 20/03835-0, 14/03989-6, 19/00860-6)

SOARES, VINICIUS REIS; SILVA MARTINS, CLARISSA; MARTINEZ, EDSON ZANGIACOMI; ARAUJO, LEONARDO DOMINGUES; ROA, SILVIA LILIANA RUIZ; SILVA, LUCAS RAVAGNANI; MOREIRA, AYRTON CUSTODIO; DE CASTRO, MARGARET. Peripheral clock system circadian abnormalities in Cushing's disease. CHRONOBIOLOGY INTERNATIONAL, v. 37, n. 6, MAY 2020. (14/03989-6)

DE SOUZA, CAMILA FERREIRA; SABEDOT, THAIS S.; MALTA, TATHIANE M.; STETSON, LINDSAY; MOROZOVA, OLENA; SOKOLOV, ARTEM; LAIRD, PETER W.; WIZNEROWICZ, MACIEJ; IAVARONE, ANTONIO; SNYDER, JAMES; et al. A Distinct DNA Methylation Shift in a Subset of Glioma CpG Island Methylator Phenotypes during Tumor Recurrence. CELL REPORTS, v. 23, n. 2, p. 637-651, APR 10 2018. (14/03989-6, 16/15485-8, 16/06488-3, 14/08321-3, 16/12329-5, 16/01975-3, 14/02245-3, 15/07925-5)

MARTINS, CLARISSA SILVA; CAMARGO, RENATA COSTA; COELI-LACCHINI, FERNANDA BORCHERS; SAGGIORO, FABIANO PINTO; MOREIRA, AYRTON CUSTODIO; DE CASTRO, MARGARET. USP8 Mutations and Cell Cycle Regulation in Corticotroph Adenomas. Hormone and Metabolic Research, v. 52, n. 2, p. 117-123, FEB 2020. (14/03989-6)

OLIVEIRA, H. A.; BUENO, A. C.; PUGLIESI, R. S.; DA SILVA JUNIOR, R. M. P.; DE CASTRO, M.; MARTINS, C. S.. PI3K inhibition by BKM120 results in anti-proliferative effects on corticotroph tumor cells. Journal of Endocrinological Investigation, JAN 2022. (14/03989-6)

MOREIRA, AYRTON CUSTODIO; ANTONINI, SONIR RAUBER; DE CASTRO, MARGARET. A sense of time of the glucocorticoid circadian clock: from the ontogeny to the diagnosis of Cushing's syndrome. EUROPEAN JOURNAL OF ENDOCRINOLOGY, v. 179, n. 1, p. R1-R18, JUL 2018. (14/03989-6, 13/09799-1)

BUENO, ANA CAROLINA; MORE, CANDY BELLIDO; MARRERO-GUTIERREZ, JUNIER; SILVA, DANILLO C. DE ALMEIDA E.; LEAL, LETICIA FERRO; MONTALDI, ANA PAULA; RAMALHO, FERNANDO SILVA; NICOLIELLO VENCIO, RICARDO ZORZETTO; DE CASTRO, MARGARET; ANTONINI, SONIR ROBERTO R.. Vitamin D receptor activation is a feasible therapeutic target to impair adrenocortical tumorigenesis. Molecular and Cellular Endocrinology, v. 558, p. 14-pg., 2022-09-02. (21/04368-9, 15/19663-5, 17/17737-7, 22/04883-3, 14/03989-6, 19/00860-6)

DOLCE, LUCIANO G.; SILVA-JUNIOR, RUI M. P.; ASSIS, LEANDRO H. P.; NASCIMENTO, ANDREY F. Z.; ARAUJO, JACKELINE S.; MESCHEDE, INGRID P.; ESPREAFICO, ENILZA M.; DE GIUSEPPE, PRISCILA O.; MURAKAMI, MARIO T.. Myosin Va interacts with the exosomal protein spermine synthase. BIOSCIENCE REPORTS, v. 39, p. 11-pg., 2019-03-29. (14/00584-5, 18/04017-9, 09/14257-8, 14/03989-6, 14/09720-9, 11/20229-7, 16/10862-8, 13/08135-2)

STECCHIN, MONICA F.; BRAID, ZILDA; MORE, CANDY B.; ARAGON, DAVI C.; CASTRO, MARGARET; MOREIRA, AYRTON C.; ANTONINI, SONIR R.. Gonadotropin-dependent pubertal disorders are common in patients with virilizing adrenocortical tumors in childhood. ENDOCRINE CONNECTIONS, v. 8, n. 5, p. 11-pg., 2019-05-01. (14/03989-6, 15/19663-5)

BODONI, ALINE FACCIOLI; COELI-LACCHINI, FERNANDA BORCHERS; GEBENLIAN, JULIANA LOURENCO; SOBRAL, LAYS MARTIN; GARCIA, CRISTIANA BERNADELLI; SILVA JUNIOR, WILSON ARAUJO; PERONNI, KAMILA CHAGAS; ZAMBELLI RAMALHO, LEANDRA NAIRA; RAMALHO, FERNANDO SILVA; MOREIRA, AYRTON C.; et al. Nicotinamide Nucleotide Transhydrogenase Is Essential for Adrenal Steroidogenesis: Clinical and In Vitro Lessons. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, v. N/A, p. 11-pg., 2022-12-07. (14/03989-6)

SOARES MOTA, JOSE ITALO; PATRICIO SILVA-JUNIOR, RUI MILTON; MARTINS, CLARISSA SILVA; BUENO, ANA CAROLINA; WILDEMBERG, LUIZ EDUARDO; DA SILVA ANTUNES, XIMENE LIMA; OKANOBO OZAKI, JORGE GUILHERME; COELI-LACCHINI, FERNANDA BORCHERS; GARCIA-PERAL, CARLOS; ROCHA OLIVEIRA, ANTONIO EDSON; et al. Telomere length and Wnt/beta-catenin pathway in adamantinomatous craniopharyngiomas. EUROPEAN JOURNAL OF ENDOCRINOLOGY, v. 187, n. 2, p. 12-pg., 2022-08-01. (19/00849-2, 14/03989-6, 19/00860-6)

PORTO DECHANDT, CARLOS ROBERTO; FERRARI, GUSTAVO DUARTE; DOS SANTOS, JONATHAS RODRIGO; CORTES DE OLIVEIRA, JOSE ANTONIO; PATRICIO SILVA-JR, RUI MILTON; SIQUEIRA CUNHA, ALEXANDRA OLIMPIO; GARCIA-CAIRASCO, NORBERTO; ALBERICI, LUCIANE CARLA. Energy Metabolism and Redox State in Brains of Wistar Audiogenic Rats, a Genetic Model of Epilepsy. FRONTIERS IN NEUROLOGY, v. 10, OCT 1 2019. (14/03989-6, 18/10089-2, 16/23509-4, 15/22327-7, 19/00849-2)

DOLCE, LUCIANO G.; SILVA-JUNIOR, RUI M. P.; ASSIS, LEANDRO H. P.; NASCIMENTO, ANDREY F. Z.; ARAUJO, JACKELINE S.; MESCHEDE, INGRID P.; ESPREAFICO, ENILZA M.; DE GIUSEPPE, PRISCILA O.; MURAKAMI, MARIO T.. Myosin Va interacts with the exosomal protein spermine synthase. BIOSCIENCE REPORTS, v. 39, n. 3, MAR 29 2019. (18/04017-9, 14/09720-9, 16/10862-8, 14/03989-6, 13/08135-2, 09/14257-8, 14/00584-5, 11/20229-7)

STECCHIN, MONICA F.; BRAID, ZILDA; MORE, CANDY B.; ARAGON, DAVI C.; CASTRO, MARGARET; MOREIRA, AYRTON C.; ANTONINI, SONIR R.. Gonadotropin-dependent pubertal disorders are common in patients with virilizing adrenocortical tumors in childhood. ENDOCRINE CONNECTIONS, v. 8, n. 5, p. 579-589, MAY 2019. (14/03989-6, 15/19663-5)

MOSELLA, MARITZA S.; SABEDOT, THAIS S.; SILVA, TIAGO C.; MALTA, TATHIANE M.; DEZEM, FELIPE SEGATO; ASMARO, KARAM P.; WELLS, MICHAEL; MUKHERJEE, ABIR; POISSON, LAILA M.; SNYDER, JAMES; et al. DNA methylation-based signatures classify sporadic pituitary tumors according to clinicopathological features. NEURO-ONCOLOGY, v. 23, n. 8, p. 1292-1303, AUG 2021. (16/11039-3, 14/03989-6, 17/10357-4)

OLIVEIRA-SANTOS, ALECIA A.; SALVATORI, ROBERTO; NOGUEIRA, MONICA C.; BUENO, ANA C.; BARROS-OLIVEIRA, CYNTHIA S.; LEAL, ANGELA C. G. B.; MARINHO, CINDI G.; DAMASCENA, NAYRA P.; OLIVEIRA, DJANE A.; MELO, MANUELA A.; et al. Enteroendocrine Connections in Congenital Isolated GH Deficiency Due to a GHRH Receptor Gene Mutation. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, v. 104, n. 7, p. 2777-2784, JUL 2019. (14/03989-6)

MERMEJO, LIVIA M.; ELIAS, PAULA C. L.; MOLINA, CARLOS A. F.; TUCCI, SILVIO; MUGLIA, VALDAIR F.; ELIAS, JORGE; ANTONINI, SONIR R.; DE CASTRO, MARGARET; MOREIRA, AYRTON C.. Early Renin Recovery After Adrenalectomy in Aldosterone-Producing Adenomas: A Prospective Study. Hormone and Metabolic Research, v. 54, n. 04, p. 8-pg., 2022-04-01. (14/03989-6, 18/10789-4)

BUENO, ANA CAROLINA; DA SILVA, RUI M. P.; STECCHINI, MONICA F.; MARRERO-GUTIERREZ, JUNIER; DE ALMEIDA E SILVA, DANILLO C.; CARDINALLI, IZILDA; SCRIDELI, CARLOS ALBERTO; JUNQUEIRA, THAIS; MOLINA, CARLOS A. F.; RAMALHO, FERNANDO SILVA; et al. DNA methylation is a comprehensive marker for pediatric adrenocortical tumors. Endocrine-Related Cancer, v. 29, n. 11, p. 15-pg., 2022-11-01. (20/03835-0, 19/00860-6, 21/04368-9, 19/00849-2, 14/03989-6)