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Identification of novel mutations on RET gene exon 8 in cases of MTC and pheocromocytoma

Grant number: 12/03242-2
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): June 01, 2012
Effective date (End): September 30, 2014
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Janete Maria Cerutti
Grantee:Larissa Valdemarin Bim
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated scholarship(s):13/06618-6 - RET p.G548V mutation identified in sporadic and hereditary pheochromocytomas: a study of prevalence and activation of MAPK pathway and metilation profile, BE.EP.MS


The RET gene is an oncogene situated on chromosome 10q11.2, it contains 21 exons and encodes a tyrosine kinase transmembrane receptor that is linked to signaling pathways involving growth, migration, and cell signaling. Activating mutations of RET in germ line cells are responsible for activation of the receptor independent of the ligand and are associated with an autosomal dominant hereditary syndrome called multiple endocrine neoplasia type 2 (MEN 2), which can be classified into three subtypes: MEN 2A, MEN 2B and familial medullary thyroid carcinoma (FMTC). Our group recently described a new heterozygous mutation in exon 8 of RET gene associated with FMTC, which leads to the replacement of a glycine for a cysteine at codon 533 (G533C). Later a member of this family presented a diagnosis of pheochromocytoma, changing the classification of the family to MEN 2A. In order to understand the genetic mechanisms associated with the penetrance of pheochromocytoma in this patient, we investigated additional mutations in the RET gene in DNA isolated from the tumor. Besides G533C RET mutation, two new mutations: G548V (exon 8) and S556T (exon 9) were identified. These data, together with the literature on mutations in exon 8 and their genotype-phenotype, suggests that they are more aggressive and more prevalent than previously imagined. Thus, this project aims to understand the overall role of RET gene mutations associated with MEN 2A syndrome identified by the group by checking their prevalence and by analyzing RET protein phosphorylation.

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