Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations

• Published in: Nature (London) Vol. 488; no. 7409; pp. 106 - 110
• Main Authors: Pugh, Trevor J., Weeraratne, Shyamal Dilhan, Archer, Tenley C., Pomeranz Krummel, Daniel A., Auclair, Daniel, Bochicchio, James, Carneiro, Mauricio O., Carter, Scott L., Cibulskis, Kristian, Erlich, Rachel L., Greulich, Heidi, Lawrence, Michael S., Lennon, Niall J., McKenna, Aaron, Meldrim, James, Ramos, Alex H., Ross, Michael G., Russ, Carsten, Shefler, Erica, Sivachenko, Andrey, Sogoloff, Brian, Stojanov, Petar, Tamayo, Pablo, Mesirov, Jill P., Amani, Vladimir, Teider, Natalia, Sengupta, Soma, Francois, Jessica Pierre, Northcott, Paul A., Taylor, Michael D., Yu, Furong, Crabtree, Gerald R., Kautzman, Amanda G., Gabriel, Stacey B., Getz, Gad, Jäger, Natalie, Jones, David T. W., Lichter, Peter, Pfister, Stefan M., Roberts, Thomas M., Meyerson, Matthew, Pomeroy, Scott L., Cho, Yoon-Jae
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.08.2012; Nature Publishing Group
• Subjects: 631/208/514/1948; 631/67/1922; 692/420/2489/68; beta Catenin - genetics; beta Catenin - metabolism; Biological and medical sciences; Cancer; Cerebellar Neoplasms - classification; Cerebellar Neoplasms - genetics; Child; DEAD-box RNA Helicases - chemistry; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Development and progression; DNA Helicases - chemistry; DNA Helicases - genetics; DNA sequencing; DNA-Binding Proteins - genetics; Exome - genetics; General aspects; Genetic aspects; Genome, Human - genetics; Hedgehog Proteins - metabolism; Histone Methyltransferases; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Humanities and Social Sciences; Humans; Intracellular Signaling Peptides and Proteins - genetics; letter; LIM Domain Proteins - genetics; Medical sciences; Medulloblastoma; Medulloblastoma - classification; Medulloblastoma - genetics; Metastasis; Models, Molecular; multidisciplinary; Mutation - genetics; Neoplasm Proteins - genetics; Neurology; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Nucleotide sequencing; Patched Receptors; Patched-1 Receptor; Physiological aspects; Promoter Regions, Genetic - genetics; Protein Structure, Tertiary - genetics; Proto-Oncogene Proteins - genetics; Receptors, Cell Surface - genetics; Repressor Proteins - genetics; Science; Signal Transduction; TCF Transcription Factors - metabolism; Transcription Factors - chemistry; Transcription Factors - genetics; Tumor Suppressor Protein p53 - genetics; Tumors of the nervous system. Phacomatoses; Wnt Proteins - metabolism; United States; Human; Nervous system diseases; Coding; Pathogenesis; Medulloblastoma; Central nervous system disease; Malignant tumor; Mutation; Catenin; Child; Cancer; Cerebral disorder
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11329

Medulloblastoma is the most common brain tumour in children; using exome sequencing of tumour samples the authors show that these cancers have low mutation rates and identify 12 significantly mutated genes, among them the gene encoding RNA helicase DDX3X. The medulloblastoma genome dissected Medulloblastoma is the most common malignant brain tumour in children. Four papers published in the 2 August 2012 issue of Nature use whole-genome and other sequencing techniques to produce a detailed picture of the genetics and genomics of this condition. Notable findings include the identification of recurrent mutations in genes not previously implicated in medulloblastoma, with significant genetic differences associated with the four biologically distinct subgroups and clinical outcomes in each. Potential avenues for therapy are suggested by the identification of targetable somatic copy-number alterations, including recurrent events targeting TGFβ signalling in Group 3, and NF-κB signalling in Group 4 medulloblastomas. Medulloblastomas are the most common malignant brain tumours in children 1 . 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 2 , 3 , 4 , 5 . 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.