Perfil molecular de um caso raro de Tumor Glioneural Formador de Rosetas na medula espinal

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Perfil molecular de um caso raro de Tumor Glioneural Formador de Rosetas na medula espinal

Quinta, 24.09.2015

O Tumor Glioneural Formador de Rosetas do IV Ventrículo (RGNT) é uma neoplasia extremamente rara, descrita em 2007 pela Organização Mundial da Saúde. É caracterizada por possuir duas porções diferentes: um componente glial, com características típicas de astrocitoma pilocítico, e um componente com rosetas neurocíticas e/ou rosetas perivasculares. Neste artigo, descrevemos um caso de um doente de 33 anos de idade com RGNT na medula espinal. Após validação por imunohistoquímica, foi feita uma extensa análise genómica, através de array-CGH (aCGH) e sequenciamento de nova geração (exoma e regiões hotspot). Observamos LOH em 1p e ganho em 1q, assim como ganho dos cromossomos 7, 9 e 16. Foram encontradas amplificações nas regiões 9q34.2 e 19p13.3, onde o gene SBNO2 está presente. Além do ganho no cromossomo 7, identificámos a presença da fusão KIAA1549:BRAF, que foi validada por RT-PCR e FISH. Foram identificadas mutações somáticas nos genes MLL2, CNNM3, PCDHGC4 e SCN1A. Estas análises sugerem que alterações na via MAPK e no metiloma, através da fusão KIAA1549:BRAF e mutação em MLL2 respectivamente, podem estar associadas ao desenvolvimento desta rara entidade tumoral.

 

Autores e afiliações:

Lucas Tadeu Bidinotto1,2, Cristovam Scapulatempo-Neto1,3*, Alan Mackay4, Gisele Caravina de Almeida3, Bernd Walter Scheithauer5, Gustavo Noriz Berardinelli1, Raul Torrieri1, Carlos Afonso Clara6, Leonir Terezinha Feltrin7, Marta Viana-Pereira8,9, Marileila Varella-Garcia10, Chris Jones4, Rui Manuel Reis1,8,9*.

1Molecular OncologyResearch Center, Barretos Cancer Hospital, Barretos, SP, Brazil

2Barretos Schoolof Health Sciences, Dr. Paulo Prata - FACISB, Barretos, SP, Brazil

3Department of Pathology, Barretos Cancer Hospital, Barretos, SP, Brazil

4Divisions of Molecular Pathology and Cancer Therapeutics, Institute for Cancer Research, London, Surrey, United Kingdom

5Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America

6Department of Neurosurgery, Barretos Cancer Hospital,Barretos, SP, Brazil

7Department of Radiology, Barretos Cancer Hospital,Barretos, SP, Brazil

8Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal

93B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal

10University of Colorado Anschutz Medical Campus | Medical Oncology/Departmentof Medicine, Aurora, Colorado, United States of America

 

Abstract:

Rosette-forming glioneuronal tumor (RGNT) of the IV ventricle is a rare and recently recognized brain tumor entity. It is histologically composed by two distinct features: a glial component, with typical characteristics of pilocytic astrocytoma, and a component forming neurocytic rosettes and/or perivascular rosettes. Herein, we describe a 33-year-old man with RGNT arising in the spinal cord. Following an immunohistochemistry validation, we further performed an extensive genomic analysis, using array-CGH (aCGH), whole exome and cancer-related hotspot sequencing, in order to better understand its underlying biology. We observed the loss of 1p and gain of 1q, as well as, gain of the whole chromosomes 7, 9 and 16. Local amplifications in 9q34.2 and 19p13.3 (encompassing the gene SBNO2) were identified. Moreover, we observed focal gains/losses in several chromosomes. Additionally, on chromosome 7, we identified the presence of the KIAA1549:BRAF gene fusion, which was further validated by RT-PCR and FISH. Across all mutational analyses, we detected and validated the somatic mutations of the genes MLL2, CNNM3, PCDHGC4 and SCN1A. Our comprehensive molecular profiling of this RGNT suggests that MAPK pathway and methylome changes, driver by KIAA1549:BRAF fusion and MLL2 mutation, respectively, could be associated with the development of this rare tumor entity.

 

Revista: Plos One

 

Link: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137690