@article{e5ee51fd497e4764b0794d16245adf85,
title = "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.",
author = "Pugh, {Trevor J.} and Weeraratne, {Shyamal Dilhan} and Archer, {Tenley C.} and {Pomeranz Krummel}, {Daniel A.} and Daniel Auclair and James Bochicchio and Carneiro, {Mauricio O.} and Carter, {Scott L.} and Kristian Cibulskis and Erlich, {Rachel L.} and Heidi Greulich and Lawrence, {Michael S.} and Lennon, {Niall J.} and {Mc Kenna}, Aaron and James Meldrim and Ramos, {Alex H.} and Ross, {Michael G.} and Carsten Russ and Erica Shefler and Andrey Sivachenko and Brian Sogoloff and Petar Stojanov and Pablo Tamayo and Mesirov, {Jill P.} and Vladimir Amani and Natalia Teider and Soma Sengupta and Francois, {Jessica Pierre} and Northcott, {Paul A.} and Taylor, {Michael D.} and Furong Yu and Crabtree, {Gerald R.} and Kautzman, {Amanda G.} and Gabriel, {Stacey B.} and Gad Getz and Natalie J{\"a}ger and Jones, {David T.W.} and Peter Lichter and Pfister, {Stefan M.} and Roberts, {Thomas M.} and Matthew Meyerson and Pomeroy, {Scott L.} and Cho, {Yoon Jae}",
note = "Funding Information: Acknowledgements This work was supported by NIH grants NHGRI U54HG003067 to E.S.Lander(E.S.,D.A.,S.B.G.,G.G.,M.M.); R01CA109467(S.L.P.,J.P.M.);R01CA105607 (H.G., T.M.R., M.M., S.L.P.); P30 HD18655 (S.L.P.); R01 CA030002 and CA050661 (T.M.R.); R01 NS046789 (G.R.C.); R01 CA154480 (P.T.); R25NS070682 (S.S.) and R01CA148699 (M.D.T.); St. Baldrick{\textquoteright}s Foundation Scholar Award and the Beirne Faculty Scholar endowment and Center for Children{\textquoteright}s Brain Tumors at Stanford University (Y.-J.C.); German Cancer Aid (109252) and the BMBF ICGC-PedBrain project (N.J.,D.T.W.J.,P.L., S.M.P.);HHMI(G.R.C.);the Pediatric BrainTumorFoundation (M.D.T.); Canadian Institutes of Health Research Fellowship (T.J.P.); Restracomp funding from the Hospital for Sick Children (P.A.N.); and the Mullarkey Research Fund (S.L.P.). We thank Children{\textquoteright}s Oncology Group and the Cooperative Human Tissue Network for providing tumour samples, the staff of the Broad Institute Biological Samples, Genome Sequencing and Genetic Analysis Platforms for their assistance in genomic processing of samples and generating the sequencing data used in this analysis,K. KehoandM.Brownat Pacific Biosciences for technicalsupport with sample barcoding methods, and L. Gaffney of Broad Institute Communications for assistance with figure layout and design.",
year = "2012",
month = aug,
day = "2",
doi = "10.1038/nature11329",
language = "English (US)",
volume = "488",
pages = "106--110",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7409",
}