| Summary: | Medulloblastoma is the most common malignant brain tumor in children. Multimodality treatment regimens involving surgery, chemotherapy and radiotherapy, have significantly
improved survival rates for this disease; however, approximately one third of patients with medulloblastoma remain incurable and current treatment result in severe
neurocognitive sequelae among long term survivors. Outcome prediction using clinical parameters and biomarkers has failed, owing to the biological heterogeneity of medulloblastomas. Molecular profiling offers an attractive approach for risk stratification of treatment and has identified at least two distinct subgroups of medulloblastoma with activation of sonic hedgehog and Wingless pathways; the remaining subgroups are poorly defined. Granule cell precursors are believed to be the cell of origin of at least a subset of medulloblastoma. Aim 1: We hypothesized that the gene expression of
medulloblastoma is possibly accounted for by not only the pathogenesis of the tumor, but also the cell of origin. We hypothesized that the medulloblastoma subgroups which
are non-sonic-hedgehog-activated arise from a different cell of origin and speculate that knowledge on the identity of the cell of origin may provide insights to the tumorigenesis of the poorly understood subgroups of tumors. We also explored independent prognostic biological markers within each molecularly distinct medulloblastoma subgroup for higher
clinical utility. Aim 2: To elucidate the role of the immune system in the biology and clinical outcome of medulloblastoma, we hypothesize that immune cells infiltrating
medulloblastoma create a unique microenvironment which may alter the tumor biology an immune-regulated gene expression signature that can be linked to prognostic
outcome.
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