Integrated Genomics Identifies Five Medulloblastoma Subtypes with Distinct Genetic Profiles, Pathway Signatures and Clinicopathological Features
Marcel Kool,Jan Koster,Jens Bunt,Nancy E. Hasselt,Arjan Lakeman,Peter van Sluis,Dirk Troost,Netteke A. Y. Schouten-van Meeteren,Huib N. Caron,Jacqueline Cloos,Alan Mrsić,Bauke Ylstra,Wiesława Grajkowska,Wolfgang Hartmann,Torsten Pietsch,David W. Ellison,Steven C. Clifford,Rogier Versteeg +17 more
TLDR
The new medulloblastoma classification presented in this study will greatly enhance the understanding of this heterogeneous disease and enable a better selection and evaluation of patients in clinical trials, and it will support the development of new molecular targeted therapies.Abstract:
Background: Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms. Methods and Findings: To get a better insight into the molecular biology of medulloblastoma we established mRNA expression profiles of 62 medulloblastomas and analyzed 52 of them also by comparative genomic hybridization (CGH) arrays. Five molecular subtypes were identified, characterized by WNT signaling (A; 9 cases), SHH signaling (B; 15 cases), expression of neuronal differentiation genes (C and D; 16 and 11 cases, respectively) or photoreceptor genes (D and E; both 11 cases). Mutations in β-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors. CGH analysis identified several fully or partly subtype-specific chromosomal aberrations. Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors. Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors. Gene expression levels faithfully reflected the chromosomal copy number changes. Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology. Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E. Patients below 3 yrs of age had type B, D, or E tumors. Type B included most desmoplastic cases. We validated and confirmed the molecular subtypes and their associated clinicopathological features with expression data from a second independent series of 46 medulloblastomas. Conclusions: The new medulloblastoma classification presented in this study will greatly enhance the understanding of this heterogeneous disease. It will enable a better selection and evaluation of patients in clinical trials, and it will support the development of new molecular targeted therapies. Ultimately, our results may lead to more individualized therapies with improved cure rates and a better quality of life.read more
Citations
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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
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
TL;DR: 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.
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.
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