Navegando por Palavras-chave "M918T"

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    Análise comparativa do perfil metabólico e funcional das variantes patogênicas G533c, C634y, M918v e M918t no gene Ret associadas à síndrome de neoplasia endócrina múltipla do tipo 2
    (Universidade Federal de São Paulo (UNIFESP), 2021) Hatanaka, Roxanne [UNIFESP]; Cerutti, Janete Maria [UNIFESP]; Universidade Federal de São Paulo
    Medullary thyroid carcinoma (MTC) is a tumor that originates from thyroid C cells, which can occur in sporadic or hereditary form. In the hereditary form, MTC is an integral part of multiple endocrine neoplasia type 2 (MEN 2) syndromes. MEN 2 is transmitted by an autosomal dominant inheritance pattern characterized by the presence of CMT (~100%), pheochromocytoma (~50%) and primary hyperparathyroidism (20-30%). The RET gene, located at 10q11.2 locus, is responsible for the predisposition to the development of the MEN 2 syndrome in approximately 98% of MEN 2 families. Due to the strong genotype-phenotype correlation in these syndromes, germline mutations in the RET gene have been used for the genetic screening of individuals at risk of developing MTC or family history of MEN 2. The American Society of Thyroid has developed a guideline (2015) for management of patients with hereditary MTC, being RET mutations 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 has been observed an intra and interfamilial phenotypic heterogeneity in the individuals carrying of specific RET mutation. Considering that mutations in the RET gene constitutively activate the MAPK pathway and that different mutations can activate different substrates, generating alteration in cellular metabolism that affect the cellular processes associated with cancer (proliferation, migration, death, survival, stress responses and among others), our hypothesis is that different mutations in the RET gene can generate different metabolites, or even variable amounts of the same metabolite, resulting in the modification of the normal cellular metabolism and, consequently, of the biological behavior of the tumor. Therefore, the aim of this study was to evaluate the metabolic profile of the HEK293 cell line transfected with the RET gene Wild type and with RET G533C, C634Y, M918V and M918T mutations using the LC-MS/MS (liquid chromatography and tandem mass spectrometry) strategy. Additionally, we analyzed the biological and biochemical behavior of pathogenic variants in the RET gene and in control, by in vitro studies The analyzed data suggest that each RET mutation has different levels of metabolites, and its production of ATP and ROS (oxygen reactive species) can be influenced by molecules and indirectly or directly correlated pathways. In addition, differences observed among the RET mutations expand the knowledge about the cellular functioning of these specific cells, in which, when compared to the clinical heterogeneity presented in these carriers, it allows us to investigate other aspects that can assist and / or improve the conduct or treatment for these individuals.
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    Early diagnosis of multiple endocrine neoplasia type 2B: a challenge for physicians
    (Sociedade Brasileira de Endocrinologia e Metabologia, 2008-11-01) Camacho, Cleber P. [UNIFESP]; Hoff, Ana O. [UNIFESP]; Lindsey, Susan C. [UNIFESP]; Signorini, Priscila S. [UNIFESP]; Valente, Flávia O. F. [UNIFESP]; Oliveira, Mariana N. L. [UNIFESP]; Kunii, Ilda S.; Biscolla, Rosa Paula M. [UNIFESP]; Cerutti, Janete Maria [UNIFESP]; Maciel, Rui Monteiro de Barros [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Fleury-Medicina e Saúde
    BACKGROUND: The hereditary form of medullary thyroid carcinoma may occur isolated as a familial medullary thyroid carcinoma (FMTC) or as part of Multiple Endocrine Neoplasia 2A (MEN2A) and 2B (MEN2B). MEN2B is a rare syndrome, its phenotype may usually, but not always, be noted by the physician. In the infant none of the MEN2B characteristics are present, except by early gastrointestinal dysfunction caused by intestinal neuromas. When available, genetic analysis confirms the diagnosis and guides pre-operative evaluation and extent of surgery. Here we report four cases of MEN2B in which the late diagnosis had a significant impact in clinical evolution and, potentially, in overall survival. CASE REPORT: We report four cases, 2 men and 2 women, with differences in their phenotypes and with a late diagnosis. The first case has a history of severe gastrointestinal obstruction requiring a surgery intervention two days after his birth. The second told had nodules in the oral mucosa and constipation since childhood. The third case referred a history of constipation from birth until 5 months of life. The fourth has had a history of chronic constipation since childhood. DISCUSSION: New concepts have emerged since the RET oncogene was identified in 1993 as the responsible gene for hereditary medullary thyroid carcinoma. The majority of MEN2B individuals have M918T mutation in the exon 16 of RET, with a few cases having a mutation A883F or the association of V804M with E805K, Y806C or S904C mutations. The consensus classifies the RET mutation in codon 918 as of highest risk and recommends total thyroidectomy and central lymph node dissection until 6 months after birth. A fast and precise diagnosis is essential to reach these goals. The identification of early manifestations such as intestinal ganglioneuromatosis and oral mucosal neuromas should prompt the physician to initiate an investigation for multiple endocrine neoplasia type 2B. CONCLUSION: The diagnosis of MEN2B is very important to allow appropriate investigation of associated diseases and to allow counseling and appropriate screening of relatives for a RET mutation. Even patients with MEN2B, which often have typical physical features, may not be properly recognized and be followed as a sporadic case. Based on this, all suspicious cases of multiple endocrine neoplasia should undergo a molecular genetic test.