ABSTRACT
There is a pressing need to identify therapeutic targets in tumors with low mutation rates such as the malignant pediatric brain tumor medulloblastoma. To address this challenge, we quantitatively profiled global proteomes and phospho-proteomes of 45 medulloblastoma samples. Integrated analyses revealed that tumors with similar RNA expression vary extensively at the post-transcriptional and post-translational levels. We identified distinct pathways associated with two subsets of SHH tumors, and found post-translational modifications of MYC that are associated with poor outcomes in group 3 tumors. We found kinases associated with subtypes and showed that inhibiting PRKDC sensitizes MYC-driven cells to radiation. Our study shows that proteomics enables a more comprehensive, functional readout, providing a foundation for future therapeutic strategies.
Subject(s)
Biomarkers, Tumor/metabolism , Brain Neoplasms/pathology , Medulloblastoma/pathology , Protein Processing, Post-Translational , Adolescent , Adult , Cell Line, Tumor , Child , Child, Preschool , DNA Methylation , DNA-Activated Protein Kinase/metabolism , Female , Gene Expression Profiling , Hedgehog Proteins/metabolism , Humans , Infant , Male , Nuclear Proteins/metabolism , Proteome/metabolism , Proteomics , Proto-Oncogene Proteins c-myc/metabolism , Sequence Analysis, RNA , Young AdultABSTRACT
Recent advances in cancer genomics have revealed 4 distinct subgroups of medulloblastomas, each with unique transcription profiles, DNA alterations and clinical outcome. Molecular classification of medulloblastomas improves predictions of clinical outcome, allowing more accurate matching of intensity of conventional treatments with chemotherapy and radiation to overall prognosis and setting the stage for the introduction of targeted therapies.
