Medulloblastoma Comprises Four Distinct Molecular Variants
Paul A. Northcott,Andrey Korshunov,Hendrik Witt,Thomas Hielscher,Charles G. Eberhart,Stephen C. Mack,Eric Bouffet,Steven C. Clifford,Cynthia Hawkins,Pim J. French,James T. Rutka,Stefan M. Pfister,Michael D. Taylor +12 more
TLDR
The authors' integrative genomics approach to a large cohort of medulloblastomas has identified four disparate subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcome.Abstract:
Purpose Recent genomic approaches have suggested the existence of multiple distinct subtypes of medulloblastoma. We studied a large cohort of medulloblastomas to determine how many subgroups of the disease exist, how they differ, and the extent of overlap between subgroups. Methods We determined gene expression profiles and DNA copy number aberrations for 103 primary medulloblastomas. Bioinformatic tools were used for class discovery of medulloblastoma subgroups based on the most informative genes in the data set. Immunohistochemistry for subgroup-specific signature genes was used to determine subgroup affiliation for 294 nonoverlapping medulloblastomas on two independent tissue microarrays. Results Multiple unsupervised analyses of transcriptional profiles identified the following four distinct, nonoverlapping molecular variants: WNT, SHH, group C, and group D. Supervised analysis of these four subgroups revealed significant subgroup-specific demographics, histology, metastatic status, and DNA copy number aberrations. Immunohistochemistry for DKK1 (WNT), SFRP1 (SHH), NPR3 (group C), and KCNA1 (group D) could reliably and uniquely classify formalin-fixed medulloblastomas in approximately 98% of patients. Group C patients (NPR3-positive tumors) exhibited a significantly diminished progression-free and overall survival irrespective of their metastatic status. Conclusion Our integrative genomics approach to a large cohort of medulloblastomas has identified four disparate subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcome. Medulloblastomas can be reliably assigned to subgroups through immunohistochemistry, thereby making medulloblastoma subclassification widely available. Future research on medulloblastoma and the development of clinical trials should take into consideration these four distinct types of medulloblastoma.read more
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Journal ArticleDOI
Molecular Subgroups of Medulloblastoma: The Current Consensus
Michael D. Taylor,Paul A. Northcott,Andrey Korshunov,Marc Remke,Marc Remke,Yoon Jae Cho,Steven C. Clifford,Charles G. Eberhart,D. Williams Parsons,Stefan Rutkowski,Amar Gajjar,David W. Ellison,Peter Lichter,Richard J. Gilbertson,Scott L. Pomeroy,Marcel Kool,Stefan M. Pfister,Stefan M. Pfister +17 more
TL;DR: It is anticipated that the molecular classification of medulloblastoma will continue to evolve and diversify in the future as larger cohorts are studied at greater depth, and herein is outlined the current consensus nomenclature, and the differences between the medullOBlastoma subgroups.
Journal ArticleDOI
TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal
Patrick J. Killela,Zachary J. Reitman,Yuchen Jiao,Chetan Bettegowda,Nishant Agrawal,Luis A. Diaz,Allan H. Friedman,Henry S. Friedman,Gary L. Gallia,Beppino C. Giovanella,Arthur P. Grollman,Tong-Chuan He,Yiping He,Ralph H. Hruban,George I. Jallo,Nils Mandahl,Alan K. Meeker,Fredrik Mertens,George J. Netto,B.K. Ahmed Rasheed,Gregory J. Riggins,Thomas A. Rosenquist,Mark Schiffman,Ie Ming Shih,Dan Theodorescu,Michael Torbenson,Victor E. Velculescu,Tian Li Wang,Nicolas Wentzensen,Laura D. Wood,Ming Zhang,Roger E. McLendon,Darell D. Bigner,Kenneth W. Kinzler,Bert Vogelstein,Nickolas Papadopoulos,Hai Yan +36 more
TL;DR: TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages and provide a biomarker that may be useful for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.
Journal ArticleDOI
Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas
Marcel Kool,Andrey Korshunov,Marc Remke,Marc Remke,David T.W. Jones,Maria Schlanstein,Paul A. Northcott,Yoon Jae Cho,Jan Koster,Antoinette Y N Schouten-van Meeteren,Dannis G. van Vuurden,Steven C. Clifford,Torsten Pietsch,André O. von Bueren,Stefan Rutkowski,Martin G. McCabe,Martin G. McCabe,V. Peter Collins,Magnus Bäcklund,Christine Haberler,Franck Bourdeaut,Olivier Delattre,François Doz,David W. Ellison,Richard J. Gilbertson,Scott L. Pomeroy,Michael D. Taylor,Peter Lichter,Stefan M. Pfister,Stefan M. Pfister +29 more
TL;DR: A meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies shows how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival.
Journal ArticleDOI
Dissecting the genomic complexity underlying medulloblastoma
David T.W. Jones,Natalie Jäger,Marcel Kool,Thomas Zichner,Barbara Hutter,Marc Sultan,Yoon Jae Cho,Trevor J. Pugh,Volker Hovestadt,Adrian M. Stütz,Tobias Rausch,Hans-Jörg Warnatz,Marina Ryzhova,Sebastian Bender,Dominik Sturm,Sabrina Pleier,Huriye Cin,Elke Pfaff,Laura Sieber,Andrea Wittmann,Marc Remke,Hendrik Witt,Hendrik Witt,Sonja Hutter,Theophilos Tzaridis,Joachim Weischenfeldt,Benjamin Raeder,Meryem Avci,Vyacheslav Amstislavskiy,Marc Zapatka,Ursula D. Weber,Qi Wang,Bärbel Lasitschka,Cynthia C. Bartholomae,Manfred Schmidt,Christof von Kalle,Volker Ast,Chris Lawerenz,Jürgen Eils,Rolf Kabbe,Vladimir Benes,Peter van Sluis,Jan Koster,Richard Volckmann,David Shih,Matthew J. Betts,Robert B. Russell,Simona Coco,Gian Paolo Tonini,Ulrich Schüller,Volkmar Hans,Norbert Graf,Yoo-Jin Kim,Camelia M. Monoranu,Wolfgang Roggendorf,Andreas Unterberg,Christel Herold-Mende,Till Milde,Till Milde,Andreas E. Kulozik,Andreas von Deimling,Andreas von Deimling,Olaf Witt,Olaf Witt,Eberhard Maass,Jochen Rössler,Martin Ebinger,Martin U. Schuhmann,Michael C. Frühwald,Martin Hasselblatt,Nada Jabado,Stefan Rutkowski,André O. von Bueren,Daniel Williamson,Steven C. Clifford,Martin G. McCabe,Martin G. McCabe,V. Peter Collins,Stephan Wolf,Stefan Wiemann,Hans Lehrach,Benedikt Brors,Wolfram Scheurlen,Jörg Felsberg,Guido Reifenberger,Paul A. Northcott,Michael D. Taylor,Matthew Meyerson,Matthew Meyerson,Scott L. Pomeroy,Scott L. Pomeroy,Marie-Laure Yaspo,Jan O. Korbel,Andrey Korshunov,Andrey Korshunov,Roland Eils,Roland Eils,Stefan M. Pfister,Stefan M. Pfister,Peter Lichter +99 more
TL;DR: An integrative deep-sequencing analysis of 125 tumour–normal pairs enhances the understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provides several potential targets for new therapeutics, especially for Group 3 and 4 patients.
Journal ArticleDOI
Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements with TP53 Mutations
Tobias Rausch,David T.W. Jones,Marc Zapatka,Adrian M. Stütz,Thomas Zichner,Joachim Weischenfeldt,Natalie Jäger,Marc Remke,David Shih,Paul A. Northcott,Elke Pfaff,Jelena Tica,Qi Wang,Luca Massimi,Hendrik Witt,Sebastian Bender,Sabrina Pleier,Huriye Cin,Cynthia Hawkins,Christian Beck,Andreas von Deimling,Volkmar Hans,Benedikt Brors,Roland Eils,Wolfram Scheurlen,Jonathon Blake,Vladimir Benes,Andreas E. Kulozik,Olaf Witt,Olaf Witt,Dianna Martin,Cindy Zhang,Rinnat Porat,Diana M. Merino,Jonathan D. Wasserman,Nada Jabado,Adam M. Fontebasso,Lars Bullinger,Frank G. Rücker,Konstanze Döhner,Hartmut Döhner,Jan Koster,Jan J. Molenaar,Rogier Versteeg,Marcel Kool,Uri Tabori,David Malkin,Andrey Korshunov,Michael D. Taylor,Peter Lichter,Stefan M. Pfister,Jan O. Korbel +51 more
TL;DR: The whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma brain tumor from a patient with a germline TP53 mutation is reported, uncovering massive, complex chromosome rearrangements and connecting p53 status and chromothripsis in specific tumor types.
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