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Authors: Pugh, Trevor J and Weeraratne, Shyamal Dilhan and Archer, Tenley C and Pomeranz Krummel, Daniel A and Auclair, Daniel and Bochicchio, James and Carneiro, Mauricio O and Carter, Scott L and Cibulskis, Kristian and Erlich, Rachel L and Greulich, Heidi and Lawrence, Michael S and Lennon, Niall J and McKenna, Aaron and Meldrim, James and Ramos, Alex H and Ross, Michael G and Russ, Carsten and Shefler, Erica and Sivachenko, Andrey and Sogoloff, Brian and Stojanov, Petar and Tamayo, Pablo and Mesirov, Jill P and Amani, Vladimir and Teider, Natalia and Sengupta, Soma and Francois, Jessica Pierre and Northcott, Paul A and Taylor, Michael D and Yu, Furong and Crabtree, Gerald R and Kautzman, Amanda G and Gabriel, Stacey B and Getz, Gad and Jäger, Natalie and Jones, David T W and Lichter, Peter and Pfister, Stefan M and Roberts, Thomas M and Meyerson, Matthew and Pomeroy, Scott L and Cho, Yoon-Jae

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, ß-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 ß-catenin signalling in medulloblastoma.

Journal: Nature
DOI: 10.1038/nature11329
Year: 2012

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