Somatic mutations activating MAPK signaling in disorders of brain overgrowth and in diffuse glioma have recently been reported in pediatric neurology. Here we developed a progressive zebrafish model of glioma based on somatic expression of oncogenes that activate MAPK-AKT signalling (H-RASG12V, K-RASG12D, AKT, EGFRv3, BRAFV600E) in neural progenitor cells. Oncogenic HRAS was the most effective in activating MAPK signaling and caused the development of different types of growth disorders in juvenile fish: from benign dysplasia/heterotopia to invasive tumors of the telencephalon, midbrain and cerebellum. We used this model to clarify the molecular events leading to malignant tumors instead of benign lesions. Specific signatures distinguish benign heterotopia from tumors and establish that tumors require persistent activation of MAPK/ERK. Moreover, analysis of global RNA expression showed that brain tumors expressed a gene signature similar to the mesenchymal glioblastoma subtype Overall design: We performed transcriptome analysis (RNA-Seq) of 3 UAS:HRASV12G brains, which carried tumorigenic lesions in the telencephalon, midbrain and IV ventricle and compared them with tumor free, age matched brains.