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

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

Author information

1
Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA; Eli and Edythe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
2
Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.
3
Eli and Edythe Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
4
Eli and Edythe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
5
Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, USA.
6
Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
7
Department of Molecular and Medical Genetics, Oregon Health and Science University (OHSU), Portland, OR, USA.
8
Harvard Medical School, Boston, MA, USA; Eli and Edythe Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital (MGH), Boston, MA, USA.
9
Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, USA.
10
CCU Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neuropathology, Heidelberg University, Heidelberg, Germany.
11
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
12
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
13
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
14
Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
15
Eli and Edythe Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: scarr@broadinstitute.org.
16
Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, USA. Electronic address: jmesirov@ucsd.edu.
17
Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Eli and Edythe Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: scott.pomeroy@childrens.harvard.edu.
18
Eli and Edythe Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. Electronic address: fraenkel-admin@mit.edu.

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

PMID:
30205044
PMCID:
PMC6372116
[Available on 2019-09-10]
DOI:
10.1016/j.ccell.2018.08.004

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