Multiple Endocrine Neoplasia type 2 (MEN 2) and Medullary Thyroid Carcinoma (TCM): new issues in developmental biology, genetics, immunology, epidemiology, mechanisms of disease and clinical management

• Grant number: 21/02752-6
• Support Opportunities: Research Projects - Thematic Grants
• Start date: March 01, 2022
• End date: February 28, 2027
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Rui Monteiro de Barros Maciel
• Grantee: Rui Monteiro de Barros Maciel
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Pesquisadores principais: João Roberto Maciel Martins ; Magnus Régios Dias da Silva
• Associated researchers: Adriano Namo Cury ; Ana Amélia Fialho de Oliveira Hoff ; Ana Luiza Silva Maia ; Bruno Fiorelini Pereira ; Carolina Ferraz da Silva ; Caroline Serrano Do Nascimento ; Celia Regina Nogueira ; Cléber Pinto Camacho ; Elisa Napolitano e Ferreira ; Fernanda Vaisman Balieiro ; Gisele Giannocco ; Gláucia Maria Ferreira da Silva Mazeto ; Helton Estrela Ramos ; Janete Maria Cerutti ; José Gilberto Henriques Vieira ; Laura Sterian ; Léa Maria Zanini Maciel ; Lidia Maria Rebolho Batista Arantes ; Lucas Leite Cunha ; Luiz Paulo Kowalski ; Marcio Abrahão ; Marcos Roberto Tavares ; Maria Cecília Martins Costa ; Maria Sharmila Alina de Sousa ; Marina Malta Letro Kizys Polisel ; Miguel Mitne Neto ; Niels Olsen Saraiva Câmara ; Ricardo Ribeiro Gama ; Rodrigo Pinheiro Araldi ; Rodrigo Portes Ureshino ; Rosa Paula Mello Biscolla ; Rosalia Do Prado Padovani ; Susan Chow Lindsey ; Valdemir Melechco Carvalho
• Associated research grant(s): 22/05221-4 - Multi-user equipment approved in grant 2021/02752-6: Automatic sequencer Seqstudio with 4 capillaries - A34274, AP.EMU
• Associated scholarship(s): 24/01435-5 - Analysis of the immune response in the microenvironment of medullary thyroid carcinoma: from the bench to clinical applications, BP.DD; 23/18438-4 - CRITICAL ANALYSIS OF CLINICAL FEATURES AND GENETIC ANCESTRY OF PATIENTS WITH MULTIPLE ENDOCRINE NEOPLASIA TYPE 2 AND CARRIERS OF THE GENETIC VARIANTS RET V804L AND RET V804M, BP.IC; 24/07948-4 - Development of animal model of MEN2 in Danio rerio ("zebrafish") to understand the mechanism associated with the development and progression of MTC and study the effect of new drugs on MTC., BP.TT; + associated scholarships 23/17908-7 - TRANSCRIPTOMIC PROFILE ANALYSIS OF THE IMMUNOLOGICAL MICROENVIRONMENT IN PATIENTS WITH MEDULLARY THYROID CARCINOMA: FROM THE LABORATORY TO CLINICAL APPLICATION., BP.IC; 23/16471-4 - DLK1 gene editing with CRISPR/Cas9 in cell lines derived from human medullary and differentiated thyroid carcinoma, BP.IC; 23/12600-4 - Econometric and Geolocated Analysis of the Implementation of Molecular Testing with RET Gene Sequencing in Patients with Medullary Thyroid Carcinoma., BP.IC; 23/12601-0 - Critical Analysis of the Impact of Second Harmonic Generation Microscopy on Medullary Thyroid Carcinoma: From Benchtop to Clinical Applications., BP.IC; 23/03161-7 - RET Gene Sequencing: study of ancestry, ethnic-geographical aspects and econometrics of the implementation of genetic diagnosis in patients with suspected Multiple Endocrine Neoplasia Type 2 in Brazil, BP.DD; 23/08780-7 - Construction and scientific exploration of a clinical and molecular database of patients investigated by BRASMEN., BP.TT; 23/02255-8 - To Improve the characterization of the variability and the genotype-phenotype correlation in patients with Multiple Endocrine Neoplasia type 2 (MEN2) and Medullary Thyroid Carcinoma "apparently sporadic" using Next Generation sequencing (NGS), BP.IC; 23/02964-9 - Development of Zebrafish (Danio rerio) model of Multiple Endocrine Neoplasia type 2 (MEN2) to study the tumor mechanism of Medullary Thyroid Cancer (MTC) and evaluate the effect of new drugs in the treatment of MTC, BP.DD; 23/02965-5 - RET gene editing via CRISPR/CAS9 in Medullary Thyroid Cancer (MTC) cell-lines, BP.DD; 23/03025-6 - Contribute to the development of an animal model of MEN2 in Danio rerio ("zebrafish") to understand the tumor mechanism of MTC and to evaluate the effect of new drugs in the treatment of MTC, BP.IC; 23/03891-5 - Contribute to the development of the gene editing model by the CRISPR/Cas9 System of RET gene mutations in Medullary Thyroid Carcinoma (MTC) cell-lines, BP.IC; 22/11388-9 - Development of animal model of MEN2 in Danio rerio ("zebrafish") to understand the mechanism associated with the development and progression of MTC and study the effect of new drugs on MTC., BP.TT; 22/13451-0 - To study the immunological processes involved in sporadic or Multiple Endocrine Neoplasm (MEN2) related Medullary Thyroid Carcinoma (MTC) and its implications in systemic immunity and tumoral microenvironment, BP.IC; 22/10804-9 - Multiple Endocrine Neoplasia type 2 (MEN 2) and Medullary Thyroid Carcinoma (TCM): new issues in developmental biology, genetics, immunology, epidemiology, mechanisms of disease and clinical management, BP.PD; 22/11509-0 - Multiple Endocrine Neoplasia type 2 (MEN 2) and Medullary Thyroid Carcinoma (TCM): new issues in developmental biology, genetics, immunology, epidemiology, mechanisms of disease and clinical management, BP.PD - associated scholarships

Abstract

Multiple Endocrine Neoplasia type 2 (MEN2) is an autosomal dominant genetic syndrome caused by germline mutations in the RET gene and represented by associations of tumors of endocrine origin, among which stands out the high penetration of medullary thyroid carcinoma (MTC). It is a complex and multifaceted disease that requires a multidisciplinary approach. Our group has contributed to the understanding of its genetics, ancestry and clinical management. This proposal - derived from questions arising from previous results of our research, as well as current and innovative questions related to MEN2 and MTC, intends to continue the previous Thematic Projects financed by FAPESP (2006/60402-1 and 2014/06570-6) that have resulted, to date, in 39 original articles and 17 Theses. To this end, we included a set of translational questions about MEN2 and MTC comprising aspects of developmental biology, mechanisms of disease, genetics, immunology, epidemiology, and clinical management, divided into 6 correlated subprojects. Subproject 1 proposes the development of an animal model of MEN2 in the fish Danio rerio ("zebrafish") to understand the tumor mechanism of MTC and to study the effect of new drugs on MTC. Subproject 2 is intended to develop a possible correction of mutations in the RET gene through gene editing by the CRISPR/Cas9 system in MTC cell lines. Subproject 3 aims to understand the systemic immunity and the tumor microenvironment of MTC with the objective to obtain an eventual immunotherapy for this type of tumor. Subproject 4 aims to expand the BrasMEN Consortium (established in the previous project) to other areas of Brazil, in order to obtain a broader view of Brazilian genotypes and phenotypes and, in addition, to answer a new set of questions related to MEN2 clinical management. Subproject 5 advances in the studies of ancestry of RET mutations inside the several Brazilian regions and seeks to compare them with other countries, considering the variations of populations and geographies. Subproject 6 proposes to further characterize the variability and genotype- phenotype correlation found in our cohort of families with MEN2 from BrasMEN cohort and patients with "apparently" sporadic MTC using strategies such as new generation genetic sequencing, bioinformatics, and data analysis in large scale available in public banks.In order to carry out these projects we have organized an experienced team of scientists with international connections. Our goal is to expand information in the area with relevant and original questions, resulting from our translational vision, the experience of our researchers, the structure installed in our laboratories and medical centers, the cohorts of patients and the knowledge accumulated over the past two decades. (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)

VALENTE, FLAVIA O. F.; CAMACHO, CLEBER P.; LINDSEY, SUSAN C.; YANG, JI H.; KUNII, ILDA S.; SANTOS, ROBERTO B.; KIZYS, MARINA M. L.; CERUTTI, JANETE M.; DIAS-DA-SILVA, MAGNUS R.; MACIEL, RUI M. B.. RET 634 germline/gonadal mosaicism generating a second pathogenic amino acid change in multiple endocrine neoplasia type 2A. AMERICAN JOURNAL OF MEDICAL GENETICS PART A, v. 194, n. 7, p. 5-pg., 2024-02-26. (06/60402-1, 13/01476-9, 14/06570-6, 21/02752-6)

DA SILVA, DANILO DIAS; ARALDI, RODRIGO PINHEIRO; BELIZARIO, MARIANA ROCHA; ROCHA, WELBERT GOMES; MACIEL, RUI MONTEIRO DE BARROS; CERUTTI, JANETE MARIA. DLK1 Is Associated with Stemness Phenotype in Medullary Thyroid Carcinoma Cell Lines. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 25, n. 22, p. 19-pg., 2024-11-01. (23/16471-4, 21/02752-6, 22/16827-0, 22/09713-9)