In silico analysis identifies a putative cell-of-origin for BRAF fusion-positive cerebellar pilocytic astrocytoma

• Published in: PloS one 2020-11, Vol.15 (11), p.e0242521-e0242521
• Main Authors: Younes, Subhi Talal, Herrington, Betty
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes; Astrocytoma; Astrocytoma - genetics; Astrocytoma - metabolism; Astrocytoma - pathology; Astrocytomas; Biology; Biology and Life Sciences; Brain; Brain Neoplasms - pathology; Brain tumors; Cancer therapies; Cell fusion; Cells (biology); Cerebellar Neoplasms - pathology; Cerebellum; Chemotherapy; Childhood cancer; Children; Computer Simulation; Databases, Genetic; Datasets; Development and progression; Female; Gene expression; Gene mapping; Gene sequencing; Genes; Genetic aspects; Genetic engineering; Humans; Male; MAP kinase; Medicine and Health Sciences; Mice; Morbidity; Mutation; Neural stem cells; Neuroglia - metabolism; Neuronal-glial interactions; Ontology; Pediatric research; Pediatrics; Progenitor cells; Progeny; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Research and Analysis Methods; Ribonucleic acid; RNA; Tumors; Ventricle; Ventricular zone; γ-Aminobutyric acid
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0242521

Childhood cancers are increasingly recognized as disorders of cellular development. This study sought to identify the cellular and developmental origins of cerebellar pilocytic astrocytoma, the most common brain tumor of childhood. Using publicly available gene expression data from pilocytic astrocytoma tumors and controlling for driver mutation, a set of developmental-related genes which were overexpressed in cerebellar pilocytic astrocytoma was identified. These genes were then mapped onto several developmental atlases in order to identify normal cells with similar gene expression patterns and the developmental trajectory of those cells was interrogated. Eight known neuro-developmental genes were identified as being expressed in cerebellar pilocytic astrocytoma. Mapping those genes or their orthologs onto mouse neuro-developmental atlases identified overlap in their expression within the ventricular zone of the cerebellar anlage. Further analysis with a single cell RNA-sequencing atlas of the developing mouse cerebellum defined this overlap as occurring in ventricular zone progenitor cells at the division point between GABA-ergic neuronal and glial lineages, a developmental trajectory which closely mirrors that previously described to occur within pilocytic astrocytoma cells. Furthermore, ventricular zone progenitor cells and their progeny exhibited evidence of MAPK pathway activation, the paradigmatic oncogenic cascade known to be active in cerebellar pilocytic astrocytoma. Gene expression from developing human brain atlases recapitulated the same anatomic localizations and developmental trajectories as those found in mice. Taken together, these data suggest this population of ventricular zone progenitor cells as the cell-of-origin for BRAF fusion-positive cerebellar pilocytic astrocytoma.