Navegando por Palavras-chave "AGK-BRAF"
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- ItemAcesso aberto (Open Access)AGK-BRAF gene fusion is a recurrent event in sporadic pediatric thyroid carcinoma(Wiley-Blackwell, 2016) Cordioli, Maria Isabel C. V. [UNIFESP]; Moraes, Lais [UNIFESP]; Carvalheira, Gianna [UNIFESP]; Sisdelli, Luiza [UNIFESP]; Alves, Maria Teresa S. [UNIFESP]; Delcelo, Rosana [UNIFESP]; Monte, Osmar; Longui, Carlos A.; Cury, Adriano N.; Cerutti, Janete M. [UNIFESP]Thyroid cancer is the fastest increasing cancer worldwide in all age groups. Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer in both adults and children. PTC genomic landscape has been extensively studied in adults, but information regarding sporadic pediatric patients is lacking. Although BRAF V600E mutation is highly prevalent in adults, this mutation is uncommon in pediatric cases. As adult and pediatric PTC is a mitogen-activated protein kinase-driven cancer, this altered pathway might be activated by different genetic events. The aim of this study was to investigate the occurrence of AGK-BRAF fusion gene, recently described in radiation-exposed pediatric PTC, in a cohort of exclusively sporadic pediatric PTC. The series consisted of 30 pediatric PTC younger than 18 years of age at the time of diagnosis and 15 matched lymph node metastases (LNM). Primary tumors and matched LNM were screened for the presence of the AGK-BRAF fusion transcript by RT-PCR. To confirm the identity of the amplified products, randomly selected samples positive for the presence of the fusion transcripts were sequenced. Moreover, BRAF dual-color, break-apart probes confirmed BRAF rearrangement. Overall, the AGK-BRAF fusion gene was detected in 10% (3/30) of primary tumors. For one of these cases, paired LNM was also available, which also shows the presence of AGK-BRAF fusion gene. This study described, for the first time, the presence of AGK-BRAF in sporadic pediatric PTC. Understanding the molecular events underlying pediatric PTC may improve preoperative diagnosis, allow molecular prognostication and define a therapeutic approach toward sporadic PTC patients.
- ItemSomente MetadadadosFusion Oncogenes Are the Main Genetic Events Found in Sporadic Papillary Thyroid Carcinomas from Children(Mary Ann Liebert, Inc, 2017) Vieira Cordioli [UNIFESP], Maria Isabel C. [UNIFESP]; Moraes, Lais [UNIFESP]; Bastos, Andre U. [UNIFESP]; Besson, Paloma [UNIFESP]; de Seixas Alves, Maria Teresa [UNIFESP]; Delcelo, Rosana [UNIFESP]; Monte, Osmar; Longui, Carlos; Cury, Adriano Namo; Cerutti, Janete M. [UNIFESP]Background: Previous studies reported significant differences in the clinical presentation and outcomes of papillary thyroid carcinoma (PTC) in pediatric patients compared with adults. Previous studies have suggested that the clinicopathological differences observed between pediatric and adult PTCs may be due the existence of distinct genetic alterations. However, the knowledge of genetic events in pediatric PTCs is based primarily on studies in radiation-exposed PTCs or in the few studies that enrolled predominantly adolescent patients. The aim of this study was to characterize the known oncogenic alterations of the MAPK pathway found in adult and radiation-exposed PTCs in a cohort of predominantly sporadic pediatric PTC patients. Methods: Thirty-five pediatric PTCs were screened for the most prevalent fusions (RET/PTC1, RET/PTC2, RET/PTC3, ETV6-NTRK3, and AGK-BRAF) and point mutations (BRAF(V600E) and NRAS(Q61)) described in sporadic pediatric PTCs. The mutational status was correlated with clinicopathological data. Results: Mutations were found in 20 out of 35 (57%) PTC cases. Fusion oncogenes were the main genetic alterations found. RET/PTC1-3 rearrangements were found in 13 (37%), ETV6-NTRK3 in 3 (9%), AGK-BRAF in 4 (11%), and BRAF(V600E) in 3 (9%). No mutation was found in NRAS(Q61). BRAF(V600E) was associated with older age and larger tumor size (p < 0.05), and RET/PTC3 was associated with a larger tumor size and multifocality (p < 0.05). Conclusions: The genetic signature in this cohort was remarkably different than that observed in adults. Although observed at a lower prevalence, the spectrum of mutations was quite similar to that described in radiation-exposed pediatric PTCs. As mutations were unidentifiable in over 40% of the PTC cases, more comprehensive studies conducted in these patients will help to decipher the genetic landscape of sporadic pediatric PTCs.
- ItemAcesso aberto (Open Access)Heterogeneidade tumoral envolvendo alterações genéticas associadas a via MAPK em Carcinomas Papilíferos da Tiroide pediátricos(Universidade Federal de São Paulo, 2021-08-03) Christiano, Yasmin Paz [UNIFESP]; Cerutti, Janete Maria [UNIFESP]; Sisdelli, Luiza; http://lattes.cnpq.br/8310429990740701; http://lattes.cnpq.br/1384038091754225; http://lattes.cnpq.br/2312418906824396Os casos de carcinoma papilífero da tiroide (CPT) têm apresentado aumento expressivo mundialmente, tanto na população pediátrica quanto na adulta. Do ponto de vista molecular, os casos de CPT apresentam uma alta prevalência de alterações genéticas cujos produtos proteicos levam à ativação da via MAPK (do inglês, Mitogen-Activated Protein Kinase). Enquanto no CPT adulto, mutações pontuais são mais comuns, na população pediátrica, as fusões gênicas são os eventos genéticos mais frequentemente observados. Em nosso grupo foi identificado pela primeira vez a fusão AGK-BRAF em casos de CPT pediátricos esporádicos, antes só observados em casos a exposição à radiação. Tem sido sugerido que entre as alterações genéticas identificadas nos casos de CPT, àquelas responsáveis por ativação da via MAPK são mutuamente exclusivas. Entretanto, nosso grupo observa uma alta prevalência de co-ocorrência de alterações genéticas responsáveis pela ativação constitutiva da via MAPK no mesmo tumor, principalmente na população pediátrica. Sendo assim, o objetivo deste trabalho foi avaliar, nos estudos que sobre CPT pediátrico, quais as alterações genéticas associadas a via MAPK nas diferentes populações e confirmar a heterogeneidade genética relacionada as fusões do tipo RET/PTC, AGK-BRA, ETV6-NTRK3 e STRN-ALK na nossa população. A casuística é constituída de 79 casos de CPT pediátricos (≤ 18 anos), provindos do Hospital São Paulo, UNIFESP, Faculdade de Ciências Médica da Santa Casa de São Paulo ou do Instituto Nacional do Câncer (INCA – RJ). As triagens das fusões foram realizadas por RT-PCR. Observamos que dos 79 casos investigados, 55 apresentaram alguma alteração genética (55/79 – 70%), sendo que, destes a grande maioria (49/79 – 62%) apresenta fusões gênica, a saber: rearranjos RET/PTC1 (28%), RET/PTC3 (15%), ETV6-NTRK3 (18%) e STRN-ALK (10%). A técnica de FISH break-apart (FISH BA) foi utilizada para confirmação da co-ocorrência das fusões em um dos casos de CPT que possui os rearranjos RET/PTC1, AGK-BRAF e STRN-ALK. Além disso, para compreendermos o mecanismo associado à instabilidade genética, avaliamos a expressão de CMYC nas amostras de CPT pediátrico. Observamos um aumento da expressão de CMYC nos casos de pacientes com menor idade ao diagnóstico de CPT. Assim, este trabalho identificou uma heterogeneidade intratumoral e a co-ocorrência de eventos genéticos que ativam a via MAPK em 24 dos casos de CPT pediátrico. A análise por FISH BA confirmou a co-ocorrência de fusões RET/PTC, AGK-BRAF e STRN-ALK em um dos casos avaliados. Por fim, resultados preliminares sugerem que o aumento da expressão de CMYC pode estar associado à instabilidade genética.