O factor de transcrição embrionário Brachyury é um novo biomarcador de agressividade e pior prognóstico em tumores do estroma gastrointestinal (GIST)

O factor de transcrição Brachyury foi recentemente descrito como estando sobre-expresso e associado com pior prógnostico em tumores sólidos. No presente estudo avaliamos o potencial valor de prognóstico de Brachyury em tumores do estroma gastrointestinal (GIST).

A expressão de Brachyury a nível proteico foi avaliada por imunohistoquimica numa série de 63 pacientes com GIST. Posteriormente, a expresão de Brachyury foi correlacionada com as características clínico-patológicas dos pacientes de forma a avaliar o impacto clínico. Alterações a nivel do DNA e mRNA foram também avaliadas através de ferramentas bioinformáticas.

Neste trabalho verificamos que Brachyury está sobre-expresso em 81.0% dos pacientes com GIST, mostrando padrões distintos de marcação a nivel subcellular: i) nuclear (4.8%), ii) citoplasmático (23.8%) e iii) nuclear e citoplasmático simultaneamente (52.4%). Especificamente, a presença de Brachyury no núcleo (com ou sem marcação citoplasmática) está associada com presença de metástases, enquanto a marcação no citoplasma está correlacionada com uma menor sobrevida.

Em conclusão, neste trabalho demonstramos pela primeira vez que Brachyury está sobre-expresso em GISTs e, consequentemente, associado com pior prognóstico. Assim, com base nestas evidências propomos que o Brachyury é um novo biomarcador de prognóstico e um potencial alvo terapêutico para tratamento de pacientes com GIST.

Autores e Afiliações:

Filipe Pinto^1,2 Nathalia C. Campanella³ Lucas F. Abrahão-Machado⁴ Cristovam Scapulatempo-Neto^3,4 Antonio T. de Oliveira^3,5 Maria J. Brito6 Raquel P. Andrade⁷ Denise P. Guimarães^3,8 Rui M. Reis^1,2,3

¹ Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal

² ICVS/3B’s-PT Government Associate Laboratory, Braga, Guimara˜es, Portugal

³ Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, Barretos CEP 14784 400, Sao Paulo, Brazil

⁴ Department of Pathology, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil

⁵ Upper Digestive Surgery Department, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil

⁶ Department of Pathology, Hospital Garcia de Orta, Almada, Portugal

⁷ Regenerative Medicine Program, Department of Medicine and Biomedical Sciences, University of Algarve, Faro, Portugal

⁸ Department of Endoscopy, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil

Abstract:

The T-box transcription factor Brachyury was recently reported to be upregulated and associated with prognosis in solid tumors. Here, we evaluate the potential use of Brachyury protein expression as a new prognostic biomarker in gastrointestinal stromal tumors (GIST). Brachyury protein expression was analyzed by immunohistochemistry in a cohort of 63 bona fide GIST patients. Brachyury expression profiles were correlated with patients’ clinicopathological features and prognostic impact. Additionally, an in silico analysis was performed using the Oncomine database to assess Brachyury alterations at DNA and mRNA levels in GISTs.

We found that Brachyury was overexpressed in the majority (81.0 %) of primary GISTs. We observed Brachyury staining in the nucleus alone in 4.8 % of cases, 23.8 % depicted only cytoplasm staining, and 52.4 % of cases exhibited both nucleus and cytoplasm immunostaining. The presence of Brachyury was associated with aggressive GIST clinicopathological features. Particularly, Brachyury nuclear (with or without cytoplasm) staining was associated with the presence of metastasis, while cytoplasm sublocalization alone was correlated with poor patient survival.

Herein, we demonstrate that Brachyury is overexpressed in GISTs and is associated with worse outcome, constituting a novel prognostic biomarker and a putative target for GIST treatment.

Revista: Gastric Cancer

Link: http://link.springer.com/article/10.1007%2Fs10120-015-0505-0