Medulloblastoma Exome Sequencing Uncovers Subtype-Specific Somatic Mutations

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Author
Weeraratne, Shyamal Dilhan
Pomeranz Krummel, Daniel A.
Auclair, Daniel
Bochicchio, James
Carneiro, Mauricio O.
Carter, Scott L.
Cibulskis, Kristian
McKenna, Aaron
Meldrim, James
Ramos, Alex H.
Ross, Michael G.
Russ, Carsten
Shefler, Erica
Sivachenko, Andrey
Stojanov, Petar
Tamayo, Pablo
Amani, Vladimir
Teider, Natalia
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.
Cho, Yoon-Jae
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/nature11329Metadata
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Pugh, Trevor J., Shyamal Dilhan Weeraratne, Tenley C. Archer, Daniel A. Pomeranz Krummel, Daniel Auclair, James Bochicchio, Mauricio O. Carneiro, et al. 2012. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 488(7409): 106-110.Abstract
Medulloblastomas are the most common malignant brain tumors in children1. 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 profiles2–5. Here, we utilized whole exome hybrid capture and deep 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, novel findings in medulloblastoma. 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 within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signaling in medulloblastoma.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413789/pdf/Terms of Use
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