Embryonal tumours of the central nervous system (CNS) represent a heterogeneous group of tumours about which little is known biologically, and whose diagnosis, on the basis of morphologic appearance alone, is controversial. Medulloblastomas, for example, are the most common malignant brain tumour of childhood, but their pathogenesis is unknown, their relationship to other embryonal CNS tumours is debated, and patients' response to therapy is difficult to predict. We approached these problems by developing a classification system based on DNA microarray gene expression data derived from 99 patient samples. Here we demonstrate that medulloblastomas are molecularly distinct from other brain tumours including primitive neuroectodermal tumours (PNETs), atypical teratoid/rhabdoid tumours (AT/RTs) and malignant gliomas. Previously unrecognized evidence supporting the derivation of medulloblastomas from cerebellar granule cells through activation of the Sonic Hedgehog (SHH) pathway was also revealed. We show further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis.

Pediatric high-grade glioma (HGG) is a devastating disease with a two-year survival of less than 20%1. We analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs) by whole genome, whole exome, and/or transcriptome sequencing. We identified recurrent somatic mutations in ACVR1 exclusively in DIPG (32%), in addition to the previously reported frequent somatic mutations in histone H3, TP53 and ATRX in both DIPG and NBS-HGGs2-5. Structural variants generating fusion genes were found in 47% of DIPGs and NBS-HGGs, with recurrent fusions involving the neurotrophin receptor genes NTRK1, 2, or 3 in 40% of NBS-HGGs in infants. Mutations targeting receptor tyrosine kinase/RAS/PI3K signaling, histone modification or chromatin remodeling, and cell cycle regulation were found in 68%, 73% and 59%, respectively, of pediatric HGGs, including DIPGs and NBS-HGGs. This comprehensive analysis provides insights into the unique and shared pathways driving pediatric HGG within and outside the brainstem.

Abstract. Nerve growth factor (NGF) and brainderived neurotrophic factor (BDNF) are molecules which regulate the development and maintenance of specific functions in different populations of peripheral and central neurons, amongst them sensory neurons of neural crest and placode origin. Under physiological conditions NGF is synthesized by peripheral target tissues, whereas BDNF synthesis is highest in the CNS. This situation changes dramatically after lesion of peripheral nerves. As previously shown, there is a marked rapid increase in NGF mRNA in the nonneuronal cells of the damaged nerve. The prolonged elevation of NGF mRNA levels is related to the immigration of activated macrophages, interleukin-1 being the most essential mediator of this effect.Here we show that transsection of the rat sciatic nerve also leads to a very marked increase in BDNF mRNA, the final levels being even ten times higher than those of NGF mRNA. However, the time-course and spatial pattern of BDNF mRNA expression are distinctly different. There is a continuous slow increase of BDNF mRNA starting after day 3 post-lesion and reaching maximal levels 3-4 wk later. These distinct differences suggest different mechanisms of regulation of NGF and BDNF synthesis in non-neuronal cells of the nerve. This was substantiated by the demonstration of differential regulation of these mRNAs in organ culture of rat sciatic nerve and Schwann cell culture. Furthermore, using bioassays and specific antibodies we showed that cultured Schwann cells are a rich source of BDNF-and ciliary neurotrophic factor (CNTF)-like neurotrophic activity in addition to NGF. Antisera raised against a BDNF-peptide demonstrated BDNF-immunoreactivity in pure cultured Schwann cells, but not in fibroblasts derived from sciatic nerve.B RAIN-derived neurotrophic factor (BDNF) l and nerve growth factor (NGF) belong to a still growing family of neurotrophic molecules collectively called neurotrophins (6, 60). These proteins show a similar basic structure reflected by conserved domains arranged around the six cysteine residues which seem to be of great importance in determining the three-dimensional structure of these molecules, a prerequisite for their biological activity. However, BDNF and NGF also show distinctly different variable domains which determine the different spectra of their neuronal specificity. Both BDNF and NGF support neural crestderived sensory neurons in the periphery (placode-derived sensory neurons are supported only by BDNF and neurotrophin-3 [NT-3]) (27,28,37). The effects of different neurotrophins on DRG neurons are additive in vitro (BDNF and NGE see reference 37; BDNF and NT-3, see reference 28), suggesting that the various sub-populations of neurons are 1. Abbreviations used in this paper: BDNF, brain-derived neurotrophic factor; DRG, dorsal root ganglion; FK, forskolin; IL-1, intefleukin-1; NGF, nerve growth factor; supported by different members of the NGF gene family in a partly overlapping manner. Under physiological as well as culture conditions NGF ...

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