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Nature DOI:10.1038/nature11329

Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations.

Publication TypeJournal Article
Year of Publication2012
AuthorsPugh, TJ, Weeraratne, SDilhan, Archer, TC, Krummel, DAPomeranz, Auclair, D, Bochicchio, J, Carneiro, MO, Carter, SL, Cibulskis, K, Erlich, RL, Greulich, H, Lawrence, MS, Lennon, NJ, McKenna, A, Meldrim, J, Ramos, AH, Ross, MG, Russ, C, Shefler, E, Sivachenko, A, Sogoloff, B, Stojanov, P, Tamayo, P, Mesirov, JP, Amani, V, Teider, N, Sengupta, S, Francois, JPierre, Northcott, PA, Taylor, MD, Yu, F, Crabtree, GR, Kautzman, AG, Gabriel, SB, Getz, G, Jäger, N, Jones, DTW, Lichter, P, Pfister, SM, Roberts, TM, Meyerson, M, Pomeroy, SL, Cho, Y-J
Date Published2012 Aug 02
Keywordsbeta Catenin, Cerebellar Neoplasms, Child, DEAD-box RNA Helicases, DNA Helicases, DNA-Binding Proteins, Exome, Genome, Human, Hedgehog Proteins, Histone-Lysine N-Methyltransferase, Humans, Intracellular Signaling Peptides and Proteins, LIM Domain Proteins, Medulloblastoma, Models, Molecular, Mutation, Neoplasm Proteins, Nuclear Proteins, Patched Receptors, Patched-1 Receptor, Promoter Regions, Genetic, Protein Structure, Tertiary, Proto-Oncogene Proteins, Receptors, Cell Surface, Repressor Proteins, Signal Transduction, TCF Transcription Factors, Transcription Factors, Tumor Suppressor Protein p53, Wnt Proteins

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.


Alternate JournalNature
PubMed ID22820256
PubMed Central IDPMC3413789
Grant ListL40 NS063706 / NS / NINDS NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
R01 NS046789 / NS / NINDS NIH HHS / United States
U54HG003067 / HG / NHGRI NIH HHS / United States
R01 CA105607 / CA / NCI NIH HHS / United States
P30 HD018655 / HD / NICHD NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
R01 CA109467 / CA / NCI NIH HHS / United States
R01 CA148699 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01CA148699 / CA / NCI NIH HHS / United States
CA050661 / CA / NCI NIH HHS / United States
R01 CA154480 / CA / NCI NIH HHS / United States
R25 NS070682 / NS / NINDS NIH HHS / United States
R01CA109467 / CA / NCI NIH HHS / United States
P30 HD18655 / HD / NICHD NIH HHS / United States
R01CA105607 / CA / NCI NIH HHS / United States
R01 CA030002 / CA / NCI NIH HHS / United States
P01 CA050661 / CA / NCI NIH HHS / United States
R25NS070682 / NS / NINDS NIH HHS / United States