title: Gene expression analyses of the spatio-temporal relationships of human medulloblastoma subgroups during early human neurogenesis.
abstract: Medulloblastoma is the most common form of malignant paediatric brain tumour and is the leading cause of childhood cancer related mortality. The four molecular subgroups of medulloblastoma that have been identified - WNT, SHH, Group 3 and Group 4 - have molecular and topographical characteristics suggestive of different cells of origin. Definitive identification of the cell(s) of origin of the medulloblastoma subgroups, particularly the poorer prognosis Group 3 and Group 4 medulloblastoma, is critical to understand the pathogenesis of the disease, and ultimately for the development of more effective treatment options. To address this issue, the gene expression profiles of normal human neural tissues and cell types representing a broad neuro-developmental continuum, were compared to those of two independent cohorts of primary human medulloblastoma specimens. Clustering, co-expression network, and gene expression analyses revealed that WNT and SHH medulloblastoma may be derived from distinct neural stem cell populations during early embryonic development, while the transcriptional profiles of Group 3 and Group 4 medulloblastoma resemble cerebellar granule neuron precursors at weeks 10-15 and 20-30 of embryogenesis, respectively. Our data indicate that Group 3 medulloblastoma may arise through abnormal neuronal differentiation, whereas deregulation of synaptic pruning-associated apoptosis may be driving Group 4 tumorigenesis. Overall, these data provide significant new insight into the spatio-temporal relationships and molecular pathogenesis of the human medulloblastoma subgroups, and provide an important framework for the development of more refined model systems, and ultimately improved therapeutic strategies.
authors.affiliation: Brain Tumour Research Program, Telethon Kids Institute, University of Western Australia, Subiaco, Western Australia, Australia; Centre of Excellence in Computational Systems Biology, ARC Centre of Excellence in Plant Energy Biology, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Hooper
authors.affiliation: Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Hawes
authors.affiliation: Division of Children's Leukaemia and Cancer Research, Telethon Kids Institute, University of Western Australia, Subiaco, Western Australia, Australia.
authors.forename: Ursula R
authors.initials: UR
authors.lastname: Kees
authors.affiliation: Brain Tumour Research Program, Telethon Kids Institute, University of Western Australia, Subiaco, Western Australia, Australia; Department of Paediatric Oncology and Haematology, Princess Margaret Hospital for Children, Subiaco, Western Australia, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Gottardo
authors.affiliation: Brain Tumour Research Program, Telethon Kids Institute, University of Western Australia, Subiaco, Western Australia, Australia.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dallas
mesh_terms: D002478:Cells, Cultured; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology*; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism