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3D Analysis of AGK-BRAF fusion of Paraffin-Embedded Sections in Pediatric Thyroid Carcinomas and High-Throughput Imaging to Study Cellular Phenotype of Cells transformed with AGK-BRAF

Grant number: 18/26395-5
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): June 09, 2019
Effective date (End): June 08, 2020
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Janete Maria Cerutti
Grantee:Luiza de Mello Oliveira Sisdelli
Supervisor: Sabine Mai
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Research place: University of Manitoba, Canada  
Associated to the scholarship:18/09911-0 - AGK-BRAF in pediatric papillary thyroid carcinoma: investigation of the mechanism associated with the high rate and functional analysis, BP.DR


In papillary thyroid carcinoma (PTC), the BRAF V600E mutation is the most prevalent alteration in adults (40%). On the other hand, in the pediatric PTC (d 18 years old), the BRAF V600E mutation is rare, and fusions involving BRAF was initially identified in radiation-exposed PTCs. Unlike the V600E mutation, the AGK-BRAF fusion is rarely identified in adult PTC. Our group showed, for the first time, that the AGK-BRAF fusion is prevalent in pediatric PTC cases. Importantly, the presence of BRAF genetic alteration is specific to PTC and was not identified in benign lesions or other thyroid tumor subtypes. Although BRAF V600E has been associated with a worse prognosis in PTC from adults, little is known about the role of BRAF alterations in pediatric PTCs. This project aims to increase our knowledge about the role of AGK-BRAF fusion by investigating the possible mechanisms associated with its high prevalence and worse prognosis in the pediatric population. To evaluate the potential mechanism associated with the high prevalence of AGK-BRAF, we will investigate the distance between these two genes and how they are arranged inside the chromosome territory (CT) in normal thyroid tissue nucleus, in pediatric and adult populations, using the DNA 3D-FISH technique. In addition, in order to understand the role of AGK-BRAF fusion in the thyroid tumor pathogenesis and cell phenotype, a normal thyroid cell line will be transfected with plasmid containing the AGK-BRAF rearrangement and, using 3D Structured Illumination Microscopy (3D-SIM), we will compare with the nucleus effects caused by the RET/PTC1, RET/PTC3, ETV6-NTRK3 and BRAF V600E alterations, also identified in pediatric thyroid tumors, and BRAF wild-type. Thus, the results from this project will help in understanding the mechanisms and the consequences of the AGK-BRAF rearrangement.

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