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Clinical impact of the use of genetic panels based on next generation sequencing in the differential diagnosis of multiple endocrine neoplasia type 1 and analysis of potential genotype-phenotype correlations.

Grant number: 16/07504-2
Support Opportunities:Regular Research Grants
Duration: September 01, 2016 - February 28, 2019
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Delmar Muniz Lourenço Jr
Grantee:Delmar Muniz Lourenço Jr
Host Institution: Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Associated researchers:Rodrigo de Almeida Toledo ; Sergio Pereira de Almeida Toledo ; Stephen J. Marx


The multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant genetic disorder, characterized by development of endocrine tumors mainly in pituitary and parathyroid glands and in endocrine cells of pancreas/duodenum. However, tumors occurring in other endocrine/non-endocrine tissues have been reported. As result, an increasing prevalence of cases suspected to MEN1 has been observed for association of MEN1-related tumors without meeting the classical criteria to the clinical diagnosis of MEN1. Also, new genetic syndromes leading to susceptibility to endocrine neoplasia have been described and an increasing association of MEN1-related tumors occurring in these neoplastic syndromes has been observed. The superposition of tumors prevents sometimes the clinical diagnosis of these genetic syndromes, reinforcing the importance of genetic diagnosis. Furthermore, the complete phenotype of these new syndromes are not completely know and new phenotypes have been described in the "old" syndromes, enhancing the importance of differential diagnosis of MEN1, MEN1-like and related states. MEN1 is caused, frequently, by germline mutation in MEN1 gene. Recently, others genes (CDKN2B/p15, CDKN2C/p18 CDKN1A/p21, CDKN1B/p27Kip1 e AIP) were associated with MEN1 or MEN1-like phenotype. The genetic diagnosis potentially changes the clinical management, therapy and genetic counselling. With the expansion of the clinical spectrum, increased clinical intersection points between genetic syndromes and discovery of new genes involved, it is necessary to establish conditions for these multiple genes be incorporated into the clinical practice, assisting in definition of the diagnosis and clinical management of these syndromes. Although "Guidelines" have recommended the analysis of the MEN1 gene and MEN1-related genes for an increasing number of clinical conditions, the introduction of these tests has not been possible in clinical practice due to the difficulties associated with Sanger sequencing (SS) (laborious work: multiple reactions by the absence of "hot spots" and multiple genes; lower cost -effectiveness). In this study, we aim to develop a broader genetic panel with nearly 30 genes that encompasses both genes associated with MEN1 and with MEN1-like phenotype and with the development of hereditary tumors in MEN1-related glands using NGS technique (Next-Generation Sequencing). This panel will allow the investigation of influences of MEN1-related genes on MEN1 phenotype in families harboring germline MEN1 mutation. This issue has not been addressed yet. The NGS is a new genetic sequencing tool more cost-effective than SS, with higher capacity and speed of data generation and with an increased gene reading coverage. With this genetic panel is intended to establish conditions to: 1) provide genetic diagnosis for MEN1, MEN1-like states and suspected cases of MEN1; 2) define the efficiency and cost-effectiveness of the genetic analysis in various medical conditions suggested for "Guidelines and not yet evaluated; 3) investigate possible interactions of these MEN1-related genes with the phenotype of MEN1; 4) allows the genetic diagnosis of various genetic syndromes which has MEN1-related tumors in our Service; 5) select appropriately cases to MLPA analysis and to exome/genome studies. Genotype-phenotype correlation analysis will be carried out in at least 250 patients with germline MEN1 mutation. In parallel, the expanded genetic panel will be tested in at least 200 patients with sporadic MEN1 phenotype, MEN1-like, MEN1-suspected or apparently sporadic MEN1-related tumors. At the end, we intend to define the clinical impact resultant from this extensive genetic analysis on different the subgroups of patients with MEN1 phenotype, MEN1-like or MEN1-related states or MEN1-suspected as or apparently sporadic MEN1-related tumors for occurrence in young age, recurrence or for tumoral multiplicity. (AU)

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Scientific publications (4)
(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)
CARVALHO, RAFAEL A.; URTREMARI, BETSAIDA; JORGE, ALEXANDER A. L.; SANTANA, LUCAS S.; QUEDAS, ELISANGELA P. S.; SEKIYA, TOMOKO; LONGUINI, VIVIANE C.; MONTENEGRO, FABIO L. M.; LERARIO, ANTONIO M.; TOLEDO, SERGIO P. A.; et al. Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing. EUROPEAN JOURNAL OF ENDOCRINOLOGY, v. 179, n. 6, p. 391-407, . (15/25444-4, 13/19810-2, 16/07504-2, 16/07965-0, 13/15388-4)
DANTAS, NAIARA C. B.; SOARES, CARLOS E. L.; MARTINS, MANOEL R. A.; LOURENCO, JR., DELMAR M.; QUIDUTE, ANA R. P.. Giant Prolactinoma Causing Hydrocephalus and Intracranial Hypertension as First Manifestations of Multiple Endocrine Neoplasia Type 1. FRONTIERS IN ENDOCRINOLOGY, v. 10, . (13/19810-2, 16/07504-2)
VAIDYA, ANAND; FLORES, SHAHIDA K.; CHENG, ZI-MING; NICOLAS, MARLO; DENG, YILUN; OPOTOWSKY, ALEXANDER R.; LOURENCO, JR., DELMAR M.; BARLETTA, JUSTINE A.; RANA, HUMA Q.; ADELAIDE PEREIRA, M.; et al. EPAS1 Mutations and Paragangliomas in Cyanotic Congenital Heart Disease. New England Journal of Medicine, v. 378, n. 13, p. 1259-1260, . (16/07504-2)
DE MENEZES MONTENEGRO, FABIO LUIZ; GUIMARAES BRESCIA, MANILLA D'ELBOUX; LOURENCO JR, DELMAR MUNIZ; ARAP, SERGIO SAMIR; D'ALESSANDRO, ANDRE FERNANDES; E SILVA FILHO, GILBERTO DE BRITTO; DE ALMEIDA TOLEDO, SERGIO PEREIRA. Could the Less-Than Subtotal Parathyroidectomy Be an Option for Treating Young Patients With Multiple Endocrine Neoplasia Type 1-Related Hyperparathyroidism?. FRONTIERS IN ENDOCRINOLOGY, v. 10, . (16/07504-2, 16/25594-9, 15/25444-4)

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