Proteomics, Post-translational Modifications, and Integrative Analyses Reveal Molecular Heterogeneity within Medulloblastoma Subgroups

• DOI: 10.1016/j.ccell.2018.08.004
• Publication Date: 2018-09-10T14:38:23Z
• Authors: Tenley C. Archer; Tobias Ehrenberger; Filip Mundt; Maxwell P. Gold; Karsten Krug; Clarence K. Mah; Elizabeth L. Mahoney; Colin J. Daniel; Alexander LeNail; Divya Ramamoorthy; Philipp Mertins; D.R. Mani; Hailei Zhang; Michael A. Gillette; Karl Clauser; Michael Noble; Lauren C. Tang; Jessica Pierre-Fr...; Jacob Silterra; James Jensen; Pablo Tamayo; Andrey Korshunov; Stefan M. Pfister; Marcel Kool; Paul A. Northcott; Rosalie C. Sears; Jonathan O. Lipton; Steven A. Carr; Jill P. Mesirov; Scott L. Pomeroy; Ernest Fraenkel
• Keywords: Male; Proteomics; 0301 basic medicine; Proteome; MYC; DNA-Activated Protein Kinase; SHH; network integration; Child; radio sensitization; Cancer; mass spectrometry; Pediatric; Tumor; Brain Neoplasms; Nuclear Proteins; Biological Sciences; 3. Good health; Child, Preschool; Female; Sequence Analysis; Biotechnology; Adult; Adolescent; Pediatric Cancer; Oncology and Carcinogenesis; 610; medulloblastoma; phospho-proteomics; Cell Line; Proto-Oncogene Proteins c-myc; Young Adult; 03 medical and health sciences; Rare Diseases; Cell Line, Tumor; Genetics; Biomarkers, Tumor; Humans; Hedgehog Proteins; Oncology & Carcinogenesis; Preschool; Protein Processing; Biomedical and Clinical Sciences; Gene Expression Profiling; Neurosciences; Post-Translational; Infant; Oncology and carcinogenesis; multi-omics; DNA Methylation; Brain Disorders; NU-7441; Brain Cancer; proteo-genomics; Orphan Drug; Biochemistry and cell biology; RNA; Protein Processing, Post-Translational; Biomarkers; Medulloblastoma

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.