Definition of Disease-Risk Stratification Groups in Childhood Medulloblastoma Using Combined Clinical, Pathologic, and Molecular Variables
David W. Ellison,Mehmet Kocak,James Dalton,James Dalton,Hisham Megahed,Hisham Megahed,Meryl E. Lusher,Meryl E. Lusher,Sarra Ryan,Sarra Ryan,Wei Zhao,Wei Zhao,SL Nicholson,SL Nicholson,Roger E. Taylor,Roger E. Taylor,Simon Bailey,Simon Bailey,Steven C. Clifford,Steven C. Clifford +19 more
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In this article, the authors evaluated clinical, pathologic, and molecular outcome indicators and stratification models in a cohort (n = 207) of patients with medulloblastoma 3 to 16 years of age from the International Society of Pediatric Oncology CNS9102 (PNET3) trial.Abstract:
Purpose Medulloblastomas are heterogeneous and include relatively good-prognosis tumors characterized by Wnt pathway activation, as well as those that cannot be successfully treated with conventional therapy. Developing a practical therapeutic stratification that allows accurate identification of disease risk offers the potential to individualize adjuvant therapy and to minimize long-term adverse effects in a subgroup of survivors. Methods Using formalin-fixed paraffin-embedded (FFPE) tissue for immunohistochemistry, fluorescent in situ hybridization, and direct sequencing to identify tumors with a Wnt pathway signature and those harboring copy number abnormalities (CNAs) of potential prognostic significance (MYC/MYCN amplification, CNAs of chromosome 6 and 17), we evaluated clinical, pathologic, and molecular outcome indicators and stratification models in a cohort (n = 207) of patients with medulloblastoma 3 to 16 years of age from the International Society of Pediatric Oncology CNS9102 (PNET3) trial. R...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
Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas
Jinghui Zhang,Gang Wu,Claudia P. Miller,Ruth G. Tatevossian,James Dalton,Bo Tang,Wilda Orisme,Chandanamali Punchihewa,Matthew Parker,Ibrahim Qaddoumi,F.A. Boop,Charles Lu,Cyriac Kandoth,Li Ding,Ryan P. Lee,Robert Huether,Xiang Chen,Erin Hedlund,Panduka Nagahawatte,Michael Rusch,Kristy Boggs,Jinjun Cheng,Jared Becksfort,Jing Ma,Guangchun Song,Yongjin Li,Lei Wei,Jianmin Wang,Sheila A. Shurtleff,John Easton,David Zhao,Robert S. Fulton,Lucinda Fulton,David J. Dooling,Bhavin Vadodaria,Heather L. Mulder,Chunlao Tang,Kerri Ochoa,Charles G. Mullighan,Amar Gajjar,Richard W. Kriwacki,Denise Sheer,Richard J. Gilbertson,Elaine R. Mardis,Richard K. Wilson,James R. Downing,Suzanne J. Baker,David W. Ellison +47 more
TL;DR: Focusing on the therapeutically challenging diffuse LGGs, this study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric L GGs and LGGNTs.
Journal ArticleDOI
Medulloblastomics: the end of the beginning
Paul A. Northcott,David T.W. Jones,Marcel Kool,Giles W. Robinson,Richard J. Gilbertson,Yoon Jae Cho,Scott L. Pomeroy,Scott L. Pomeroy,Andrey Korshunov,Peter Lichter,Michael D. Taylor,Stefan M. Pfister,Stefan M. Pfister +12 more
TL;DR: The availability of next-generation sequencing and complementary high-density genomic technologies has unmasked novel driver mutations in each medulloblastoma subgroup, pinpointing previously unappreciated diagnostic and therapeutic targets.
Journal ArticleDOI
Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups
David W. Ellison,James Dalton,Mehmet Kocak,SL Nicholson,Charles H. Fraga,Geoff Neale,Anna M. Kenney,Daniel J. Brat,Arie Perry,William H. Yong,Roger E. Taylor,Simon Bailey,Steven C. Clifford,Richard J. Gilbertson +13 more
TL;DR: A robust method for detecting SHH, WNT, and non-SHH/WNT molecular subgroups in formalin-fixed medulloblastoma samples is described and the first outcome data based on a clinical trial cohort and novel data on how molecular sub groups are distributed across the range of disease are provided.
Journal ArticleDOI
Risk stratification of childhood medulloblastoma in the molecular era: the current consensus
Vijay Ramaswamy,Marc Remke,Eric Bouffet,Simon Bailey,Steven C. Clifford,François Doz,Marcel Kool,Christelle Dufour,Gilles Vassal,Till Milde,Olaf Witt,Katja von Hoff,Torsten Pietsch,Paul A. Northcott,Amar Gajjar,Giles W. Robinson,Laetitia Padovani,Nicolas André,Maura Massimino,Barry Pizer,Roger J. Packer,Stefan Rutkowski,Stefan M. Pfister,Michael D. Taylor,Scott L. Pomeroy +24 more
TL;DR: A consensus can serve as an outline for prioritization of certain molecular subsets of tumors to define and validate risk groups as a basis for future clinical trials.
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Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial
Amar Gajjar,Murali Chintagumpala,David M. Ashley,Stewart J. Kellie,Larry E. Kun,Thomas E. Merchant,S.Y. Woo,Greg Wheeler,Valerie Ahern,Matthew J. Krasin,Maryam Fouladi,Alberto Broniscer,Robert A. Krance,Gregory A. Hale,Clinton F. Stewart,Robert C. Dauser,Robert A. Sanford,Christine E. Fuller,Ching C. Lau,James M. Boyett,Dana Wallace,Richard J. Gilbertson +21 more
TL;DR: Investigating the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma found it can be used to improve the outcome of patients with high-risk medullOBlastoma.
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Roger J. Packer,Amar Gajjar,Gilbert Vezina,Lucy B. Rorke-Adams,Peter C. Burger,Patricia L. Robertson,Lisa Bayer,Deborah Lafond,Bernadine Donahue,Mary Anne H. Marymont,Karin M. Muraszko,James Langston,Richard Sposto +12 more
TL;DR: An encouraging EFS rate for children with nondisseminated MB treated with reduced-dose craniospinal radiation and chemotherapy is disclosed and additional, careful, step-wise reductions in CSRT in adequately staged patients may be possible.
Journal ArticleDOI
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
TL;DR: 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.
Journal ArticleDOI
Genomics Identifies Medulloblastoma Subgroups That Are Enriched for Specific Genetic Alterations
Margaret C. Thompson,Christine E. Fuller,Twala L. Hogg,James T. Dalton,David Finkelstein,Ching C. Lau,Murali Chintagumpala,Adekunle M. Adesina,David M. Ashley,Stewart J. Kellie,Michael D. Taylor,Tom Curran,Amar Gajjar,Richard J. Gilbertson +13 more
TL;DR: Genome-wide expression profiles can partition large tumor cohorts into subgroups that are enriched for specific genetic alterations that may assist ultimately in the selection of patients for future clinical trials of molecular targeted therapies.
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