Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations.

Abstract	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.
Authors	Trevor J Pugh, Shyamal Dilhan Weeraratne, Tenley C Archer, Daniel A Pomeranz Krummel, Daniel Auclair, James Bochicchio, Mauricio O Carneiro, Scott L Carter, Kristian Cibulskis, Rachel L Erlich, Heidi Greulich, Michael S Lawrence, Niall J Lennon, Aaron McKenna, James Meldrim, Alex H Ramos, Michael G Ross, Carsten Russ, Erica Shefler, Andrey Sivachenko, Brian Sogoloff, Petar Stojanov, Pablo Tamayo, Jill P Mesirov, Vladimir Amani, Natalia Teider, Soma Sengupta, Jessica Pierre Francois, Paul A Northcott, Michael D Taylor, Furong Yu, Gerald R Crabtree, Amanda G Kautzman, Stacey B Gabriel, Gad Getz, Natalie Jäger, David T W Jones, Peter Lichter, Stefan M Pfister, Thomas M Roberts, Matthew Meyerson, Scott L Pomeroy, Yoon-Jae Cho
Journal	Nature (Nature) Vol. 488 Issue 7409 Pg. 106-10 (Aug 02 2012) ISSN: 1476-4687 [Electronic] England
PMID	22820256 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	BCOR protein, human CTNNB1 protein, human DNA-Binding Proteins GPS2 protein, human Hedgehog Proteins Intracellular Signaling Peptides and Proteins KMT2D protein, human LDB1 protein, human LIM Domain Proteins Neoplasm Proteins Nuclear Proteins PTCH1 protein, human Patched Receptors Patched-1 Receptor Proto-Oncogene Proteins Receptors, Cell Surface Repressor Proteins SHH protein, human TCF Transcription Factors TP53 protein, human Transcription Factors Tumor Suppressor Protein p53 Wnt Proteins beta Catenin Histone Methyltransferases Histone-Lysine N-Methyltransferase DDX3X protein, human SMARCA4 protein, human DNA Helicases DEAD-box RNA Helicases
Topics	Cerebellar Neoplasms (classification, genetics) Child DEAD-box RNA Helicases (chemistry, genetics, metabolism) DNA Helicases (chemistry, genetics) DNA-Binding Proteins (genetics) Exome (genetics) Genome, Human (genetics) Hedgehog Proteins (metabolism) Histone Methyltransferases Histone-Lysine N-Methyltransferase (genetics, metabolism) Humans Intracellular Signaling Peptides and Proteins (genetics) LIM Domain Proteins (genetics) Medulloblastoma (classification, genetics) Models, Molecular Mutation (genetics) Neoplasm Proteins (genetics) Nuclear Proteins (chemistry, genetics) Patched Receptors Patched-1 Receptor Promoter Regions, Genetic (genetics) Protein Structure, Tertiary (genetics) Proto-Oncogene Proteins (genetics) Receptors, Cell Surface (genetics) Repressor Proteins (genetics) Signal Transduction TCF Transcription Factors (metabolism) Transcription Factors (chemistry, genetics) Tumor Suppressor Protein p53 (genetics) Wnt Proteins (metabolism) beta Catenin (genetics, metabolism)

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