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

Cancer Cell. 2018 Sep 10;34(3):396-410.e8. doi: 10.1016/j.ccell.2018.08.004.

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.

Keywords: MYC; NU-7441; SHH; mass spectrometry; medulloblastoma; multi-omics; network integration; phospho-proteomics; proteo-genomics; radio sensitization.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Biomarkers, Tumor / metabolism*
  • Brain Neoplasms / pathology*
  • Cell Line, Tumor
  • Child
  • Child, Preschool
  • DNA Methylation
  • DNA-Activated Protein Kinase / metabolism
  • Female
  • Gene Expression Profiling
  • Hedgehog Proteins / metabolism
  • Humans
  • Infant
  • Male
  • Medulloblastoma / pathology*
  • Nuclear Proteins / metabolism
  • Protein Processing, Post-Translational*
  • Proteome / metabolism
  • Proteomics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Sequence Analysis, RNA
  • Young Adult

Substances

  • Biomarkers, Tumor
  • Hedgehog Proteins
  • MYC protein, human
  • Nuclear Proteins
  • Proteome
  • Proto-Oncogene Proteins c-myc
  • SHH protein, human
  • DNA-Activated Protein Kinase
  • PRKDC protein, human