| Grant number: | 12/06221-6 |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |
| Effective date (Start): | May 01, 2012 |
| Effective date (End): | May 05, 2016 |
| Field of knowledge: | Biological Sciences - Genetics - Human and Medical Genetics |
| Principal Investigator: | Janete Maria Cerutti |
| Grantee: | André Uchimura Bastos |
| Host Institution: | Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil |
| Associated scholarship(s): | 12/23234-4 - Functional characterization of BRAFV600E and RET/PTC double mutation and methylation profiling in in vitro model and thyroid tumors, BE.EP.DD |
Abstract The Papillary Thyroid Carcinoma (PTC) is the most common histological subtype of thyroid tumors. Alterations in genes coding for the MAPK pathway plays a crucial role in its pathogenesis, and mutations in the BRAF and RAS oncogenes and rearrangements involving the RET oncogene are the most frequent. The recognition of these alterations and the association studies can lead to the most efficient therapy to each patient, especially with target drug therapy. Our group investigated the prevalence of RET/PTC rearrangements and BRAFV600E mutation in a series of PTC (n=118) and correlated with clinical-pathological features and expression profile. This analysis identified the co-occurrence of BRAFV600E mutation and RET/PTC rearrangements in approximately 13% of the cases, and RET/PTC3 isoform occurred in 87%. These data have important clinical implications regarding prognosis and treatment of patients. Thus, by functional analysis, we decided to investigate the effect of the two mutations in the biological characteristics of Nthy-ori-3-1 cells (immortal normal thyroid follicular cell). For this, Nthy-ori-3-1 cells will be transfected with expression vectors containing BRAF V600E, RET/PTC3 concomitant and control vectors containing BRAF V600E, RET/PTC3 or the empty vector. We will analyze the expression of iodine's metabolism genes (NIS, TSHR, TPO, TG and PDS), and the activation of MAPK and PI3K/AKT/mTOR pathways, as well as growth and viability, cell cycle regulation, apoptosis, anchorage-independent growth and the level of genetic instability by the formation of DSBs (double strand breaks). Later, we also will analyze the effect of BRAF-targeted drugs, as it was reported that the simultaneous presence of mutations in BRAF and RAS induced resistance in melanoma cells. These analyzes will allow a better understanding of the pathogenesis of PTC, as well as in deciding the better therapy for patients with the different mutations. (AU) | |
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