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Study Description

Medulloblastomas are the most common malignant brain tumors in children. Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles. Here, we utilized whole exome hybrid capture and Illumina sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas exhibit low mutation rates consistent with other pediatric tumors, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR, and LDB1, to our knowledge novel findings in medulloblastoma and all cancer. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant but not wild type beta-catenin. Together, our study reveals the alteration of Wnt, Hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signaling in medulloblastoma.


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Publicly Available Data
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Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Exome Sequencing Agilent Agilent selected, 76bp paired end reads N/A N/A
Study History

Updated to study version 2 (October 2013): n=8 subjects have been removed; n=10 subjects have been added.

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Study Attribution
  • Principal Investigators
    • Matthew Meyerson. Broad Institute, Cambridge MA, Dana Farber Cancer Institute, Boston, MA, USA.
    • Scott Pomeroy. Children's Hospital, Boston, MA, USA.
    • Yoon-Jae Cho. Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, CA, USA.
  • Funding Sources
    • U54HG003067I. National Human Research Institute, National Institutes of Health, Bethesda, MD, USA.
    • R01CA109467. National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
    • R01CA105607. National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
    • P30 HD18655. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.