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author 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
author_facet 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
author_sort Pugh, Trevor J.
collection PubMed
description Medulloblastomas are the most common malignant brain tumors in children(1). Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles(2–5). Here, we utilized whole exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas exhibit low mutation rates consistent with other pediatric tumors, 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 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, novel findings in medulloblastoma. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant but not wild type beta-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 beta-catenin signaling in medulloblastoma.
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spelling pubmed-34137892013-02-02 MEDULLOBLASTOMA EXOME SEQUENCING UNCOVERS SUBTYPE-SPECIFIC SOMATIC MUTATIONS 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 Nature Article Medulloblastomas are the most common malignant brain tumors in children(1). Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles(2–5). Here, we utilized whole exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas exhibit low mutation rates consistent with other pediatric tumors, 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 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, novel findings in medulloblastoma. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant but not wild type beta-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 beta-catenin signaling in medulloblastoma. 2012-08-02 /pmc/articles/PMC3413789/ /pubmed/22820256 http://dx.doi.org/10.1038/nature11329 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
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
MEDULLOBLASTOMA EXOME SEQUENCING UNCOVERS SUBTYPE-SPECIFIC SOMATIC MUTATIONS
title MEDULLOBLASTOMA EXOME SEQUENCING UNCOVERS SUBTYPE-SPECIFIC SOMATIC MUTATIONS
title_full MEDULLOBLASTOMA EXOME SEQUENCING UNCOVERS SUBTYPE-SPECIFIC SOMATIC MUTATIONS
title_fullStr MEDULLOBLASTOMA EXOME SEQUENCING UNCOVERS SUBTYPE-SPECIFIC SOMATIC MUTATIONS
title_full_unstemmed MEDULLOBLASTOMA EXOME SEQUENCING UNCOVERS SUBTYPE-SPECIFIC SOMATIC MUTATIONS
title_short MEDULLOBLASTOMA EXOME SEQUENCING UNCOVERS SUBTYPE-SPECIFIC SOMATIC MUTATIONS
title_sort medulloblastoma exome sequencing uncovers subtype-specific somatic mutations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413789/
https://www.ncbi.nlm.nih.gov/pubmed/22820256
http://dx.doi.org/10.1038/nature11329
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