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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, ?-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 ?-catenin signalling in medulloblastoma.

SUBMITTER: Pugh TJ 

PROVIDER: S-EPMC3413789 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations.

Pugh Trevor J TJ   Weeraratne Shyamal Dilhan SD   Archer Tenley C TC   Pomeranz Krummel Daniel A DA   Auclair Daniel D   Bochicchio James J   Carneiro Mauricio O MO   Carter Scott L SL   Cibulskis Kristian K   Erlich Rachel L RL   Greulich Heidi H   Lawrence Michael S MS   Lennon Niall J NJ   McKenna Aaron A   Meldrim James J   Ramos Alex H AH   Ross Michael G MG   Russ Carsten C   Shefler Erica E   Sivachenko Andrey A   Sogoloff Brian B   Stojanov Petar P   Tamayo Pablo P   Mesirov Jill P JP   Amani Vladimir V   Teider Natalia N   Sengupta Soma S   Francois Jessica Pierre JP   Northcott Paul A PA   Taylor Michael D MD   Yu Furong F   Crabtree Gerald R GR   Kautzman Amanda G AG   Gabriel Stacey B SB   Getz Gad G   Jäger Natalie N   Jones David T W DT   Lichter Peter P   Pfister Stefan M SM   Roberts Thomas M TM   Meyerson Matthew M   Pomeroy Scott L SL   Cho Yoon-Jae YJ  

Nature 20120801 7409


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 codin  ...[more]

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