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Investigation of molecular markers for the diagnosis of MEN 2 through metabolic profile of HEK293 cells with RET expression and MEN 2/RET patients

Grant number: 17/12107-5
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): April 01, 2018
Effective date (End): May 31, 2020
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Janete Maria Cerutti
Grantee:Roxanne Hatanaka
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated research grant:14/06570-6 - Comprehensive whole exome, paired-end RNA and genome sequencing: new insights into genetic bases of thyroid carcinoma in pediatric and adult ages and applications in clinical practice, AP.TEM


Medullary Thyroid Carcinoma (MTC) is a tumor that originates from thyroid C cells, which can occur sporadic or hereditary. In the hereditary form, MTC is an integral part of Multiple Endocrine Neoplasia type 2 (MEN 2) Syndromes. MEN 2 is an autosomal dominant inheritance pattern characterized by the presence of CMT (95-100%), pheochromocytoma (50%) and primary hyperparathyroidism (30%). Mutations in the RET gene located on chromosome 10q11 have been identified in approximately 95-98% of MEN 2 families. Due to the strong genotype-phenotype correlation found in these syndromes, mutations in the RET gene have been used for the genetic screening of individuals or family members at risk of developing MTC, as well as in the prognosis. In fact, the American Society of Thyroid has developed a guideline (2015) for management of patients with hereditary MTC. Mutations were classified according to the risk of aggressiveness of MTC, which is progressive. According to the risk (high, higher or highest), the age of prophylactic thyroidectomy is suggested. Despite the strong genotype-phenotype correlation in the MEN 2 syndrome, there are still questions about the clinical heterogeneity observed in the families and between the families with the same mutation in the RET gene. Knowing that mutations in the RET gene activate the MAPK pathway and that the different mutations can activate different substrates, which may consequently alter the intracellular metabolism and affect the cellular processes associated with Cancer such as proliferation, migration, death, survival, stress responses and others, our hypothesis is that different mutations in the RET gene can generate different metabolites, or even variable amounts of the same metabolite, that will produce distinct effects on the cellular phenotype. Therefore, the aim of this study is to analyze the metabolites produced in HEK cells after transformation with the RET wild type gene or with the G533C, C634R, C634Y, Y791F, C634Y/Y791F double, M918T and M918V mutations in RET gene. We also intend to analyze the plasmas of patients with MEN 2 and the presence of RET mutations evaluated in the in vitro study. The metabolic profile will be evaluated by LC-MS/MS (Liquid Chromatography and Tandem Mass Spectrometry). We hope to identify metabolites that may elucidate the biological behavior of the tumor and the observed clinical heterogeneity. In addition, it is expected that these identified metabolites can be used as molecular markers in the follow-up of patients with MEN 2 and in the identification of metabolic pathways associated with drug progression or resistance. (AU)

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