Scientific Publications

Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations.

Publication TypeJournal Article
AuthorsPugh, TJ, Weeraratne SD, Archer TC, Pomeranz Krummel DA, 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., Stojanov P., Tamayo P., Mesirov J. P., Amani V., Sengupta S., Northcott PA, Taylor MD, Yu F., Crabtree GR, Gabriel SB, Getz G., Jäger N., Jones DT, Lichter P., Pfister SM, Roberts TM, Meyerson M., Pomeroy SL, and Cho YJ
AbstractMedulloblastomas 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.
Year of Publication2012
JournalNature
Volume488
Issue7409
Pages106-10
Date Published (YYYY/MM/DD)2012/08/02
ISSN Number0028-0836
DOI10.1038/nature11329
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/22820256?dopt=Abstract