Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations
Open accessAbstract
Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, 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 newly 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. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, β-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic β-catenin signalling in medulloblastoma.
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- Authors
- Pugh, T. J., Weeraratne, S. D., Archer, T. C., Pomeranz Krummel, D. A., Auclair, D., Bochicchio, J., Carneiro, M. O., Carter, S. L., Cibulskis, K., Erlich, R. L., Greulich, H., Lawrence, M. S., Lennon, N. J., McKenna, A., Meldrim, J., Ramos, A. H., Ross, M. G., Russ, C., Shefler, E., Sivachenko, A., Sogoloff, B., Stojanov, P., Tamayo, P., Mesirov, J. P., Amani, V., Teider, N., Sengupta, S., Francois, J. P., Northcott, P. A., Taylor, M. D., Yu, F., Crabtree, G. R., Kautzman, A. G., Gabriel, S. B., Getz, G., Jäger, N., Jones, D. T. W., Lichter, P., Pfister, S. M., Roberts, T. M., Meyerson, M., Pomeroy, S. L., & Cho, Y.-J.
- Affiliations
- Broad Institute (US)
- Boston Children's Hospital (US)
- Hospital for Sick Children (CA)
- Stanford Medicine (US)
- Howard Hughes Medical Institute (US)
- German Cancer Research Center (DE)
- Harvard University (US)
- Corresponding author
- Meyerson, Matthew
- Pomeroy, Scott L.
- Cho, Yoon-Jae
- ORCID
- Pugh, Trevor J.
- Archer, Tenley C.
- Auclair, Daniel
- Carter, Scott L.
- Cibulskis, Kristian
- Greulich, Heidi
- Lawrence, Michael S.
- Lennon, Niall J.
- McKenna, Aaron
- Meldrim, James
- Sivachenko, Andrey
- Tamayo, Pablo
- Mesirov, Jill P.
- Amani, Vladimir
- Sengupta, Soma
- Northcott, Paul A.
- Taylor, Michael D.
- Yu, Furong
- Crabtree, Gerald R.
- Kautzman, Amanda G.
- Gabriel, Stacey B.
- Getz, Gad
- Jäger, Natalie
- Jones, David T. W.
- Lichter, Peter
- Pfister, Stefan M.
- Roberts, Thomas M.
- Meyerson, Matthew
- Pomeroy, Scott L.
- Cho, Yoon-Jae
- Venue
- Nature
- Published
- 2012-07-22
- Volume
- 488
- Issue
- 7409
- Pages
- 106-110
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3413789
- OpenAlex
- W1979855662
- Cited by
- 750
- References
- 29
- Citations by year
- 2026: 8 · 2025: 28 · 2024: 23 · 2023: 38 · 2022: 37 · 2021: 51 · 2020: 43 · 2019: 46 · 2018: 60 · 2017: 57 · 2016: 72 · 2015: 77 · 2014: 94 · 2013: 93 · 2012: 21
- FWCI
- 43.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Canadian Institutes of Health Research
- National Human Genome Research Institute (U54HG003067)
- National Cancer Institute (R01CA148699, CA050661, R01CA030002, R01CA154480, R01CA109467, P01CA050661, R01CA105607)
- National Institute of Neurological Disorders and Stroke (L40 NS063706, R25NS070682, R01NS046789)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- medulloblastoma, somatic mutations, DDX3X, RNA helicase, CTNNB1, β-catenin, Wnt signaling, TGF-beta signaling, NF-κB signaling, GPS2, BCOR, LDB1, somatic copy number alterations, pediatric brain tumors
- MeSH terms
- Patched Receptors, Patched-1 Receptor, Histone Methyltransferases, Cerebellar Neoplasms, Child, DNA Helicases, DNA-Binding Proteins, Humans, Medulloblastoma, Models, Molecular, Mutation, Neoplasm Proteins, Nuclear Proteins, Promoter Regions, Genetic, Histone-Lysine N-Methyltransferase, Proto-Oncogene Proteins, Receptors, Cell Surface, Repressor Proteins, Transcription Factors, Signal Transduction, Genome, Human, Tumor Suppressor Protein p53, Protein Structure, Tertiary, Intracellular Signaling Peptides and Proteins, Wnt Proteins, beta Catenin, TCF Transcription Factors, DEAD-box RNA Helicases, Hedgehog Proteins, Exome, LIM Domain Proteins
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