Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma

Alan Mackay; Anna Burford; Diana Carvalho; Elisa Izquierdo; Janat Fazal-Salom; Kathryn R. Taylor; Lynn Bjerke; Matthew Clarke; Mara Vinci; Meera Nandhabalan; Sara Temelso; Sergey Popov; Valeria Molinari; Pichai Raman; Angela J. Waanders; Harry J. Han; Saumya Gupta; Lynley Marshall; Stergios Zacharoulis; Sucheta Vaidya; Henry C. Mandeville; Leslie R. Bridges; Andrew J. Martin; Safa Al-Sarraj; Christopher Chandler; Ho-Keung Ng; Xingang Li; Kun Mu; Saoussen Trabelsi; Dorra H’mida-Ben Brahim; Alexei N. Kisljakov; Dmitry M. Konovalov; Andrew S. Moore; Angel Montero Carcaboso; Mariona Sunol; Carmen de Torres; Ofelia Cruz; Jaume Mora; Ludmila I. Shats; João N. Stavale; Lucas T. Bidinotto; Rui M. Reis; Natacha Entz-Werle; Michael Farrell; Jane Cryan; Darach Crimmins; John Caird; Jane Pears; Michelle Monje; Marie-Anne Debily; David Castel; Jacques Grill; Cynthia Hawkins; Hamid Nikbakht; Nada Jabado; Suzanne J. Baker; Stefan M. Pfister; David T.W. Jones; Maryam Fouladi; André O. von Bueren; Michael Baudis; Adam Resnick; Chris Jones

doi:10.1016/j.ccell.2017.08.017

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Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma

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Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma

Alan Mackay, Anna Burford, Diana Carvalho, Elisa Izquierdo, Janat Fazal-Salom, Kathryn R. Taylor, Lynn Bjerke, Matthew Clarke, Mara Vinci, Meera Nandhabalan, …

Cancer cell, Vol.32(4), pp.520-537.e5

09/10/2017

DOI: https://doi.org/10.1016/j.ccell.2017.08.017

PMCID: PMC5637314

PMID: 28966033

Abstract

DIPG

exome

genome

glioblastoma

histone

methylation

We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification. [Display omitted] •Pediatric HGG and DIPG comprise a diverse set of clinical and biological subgroups•Somatic coding mutations per tumor range from none to among the highest seen in human cancer•Histone mutations co-segregate with distinct alterations and downstream pathways•H3/IDH1 WT tumors may resemble low-grade lesions and have targetable alterations Mackay et al. perform an integrated analysis of >1,000 cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma. They identify co-segregating mutations in histone-mutant subgroups and show that histone wild-type subgroups are molecularly more similar to lower-grade tumors.

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Title: Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma
Creators - without role: Alan Mackay - Institute of Cancer Research
Anna Burford - Institute of Cancer Research
Diana Carvalho - Institute of Cancer Research
Elisa Izquierdo - Institute of Cancer Research
Janat Fazal-Salom - Institute of Cancer Research
Kathryn R. Taylor - Division of Molecular Pathology, The Institute of Cancer Research, London, UK
Lynn Bjerke - Institute of Cancer Research
Matthew Clarke - Institute of Cancer Research
Mara Vinci - Institute of Cancer Research
Meera Nandhabalan - Institute of Cancer Research
Sara Temelso - Institute of Cancer Research
Sergey Popov - Institute of Cancer Research
Valeria Molinari - Institute of Cancer Research
Pichai Raman - Children's Hospital of Philadelphia
Angela J. Waanders - Children's Hospital of Philadelphia
Harry J. Han - Children's Hospital of Philadelphia
Saumya Gupta - SIB Swiss Institute of Bioinformatics
Lynley Marshall - Royal Marsden NHS Foundation Trust
Stergios Zacharoulis - Royal Marsden NHS Foundation Trust
Sucheta Vaidya - Royal Marsden NHS Foundation Trust
Henry C. Mandeville - Royal Marsden NHS Foundation Trust
Leslie R. Bridges - St George's Hospital
Andrew J. Martin - St George's Hospital
Safa Al-Sarraj - King's College - North Carolina
Christopher Chandler - King's College - North Carolina
Ho-Keung Ng - Chinese University of Hong Kong
Xingang Li - Shandong University
Kun Mu - Shandong University
Saoussen Trabelsi - Department of Cytogenetics and Reproductive Biology, Farhat Hached Hospital, Sousse, Tunisia
Dorra H’mida-Ben Brahim - Department of Cytogenetics and Reproductive Biology, Farhat Hached Hospital, Sousse, Tunisia
Alexei N. Kisljakov - Boston Children's Hospital
Dmitry M. Konovalov - Department of Pathology, Dmitrii Rogachev Research and Clinical Centre of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
Andrew S. Moore - University of Queensland
Angel Montero Carcaboso - Institut de Recerca Sant Joan de Deu, Barcelona, Spain
Mariona Sunol - Institut de Recerca Sant Joan de Deu, Barcelona, Spain
Carmen de Torres - Institut de Recerca Sant Joan de Deu, Barcelona, Spain
Ofelia Cruz - Institut de Recerca Sant Joan de Deu, Barcelona, Spain
Jaume Mora - Institut de Recerca Sant Joan de Deu, Barcelona, Spain
Ludmila I. Shats - Saint Petersburg State Pediatric Medical University
João N. Stavale - Universidade Federal de São Paulo
Lucas T. Bidinotto - Molecular Oncology Research Centre, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
Rui M. Reis - Molecular Oncology Research Centre, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
Natacha Entz-Werle - Pédiatrie Onco-Hématologie - Pédiatrie III, Centre Hospitalier Régional et Universitaire Hautepierre, Strasbourg, France
Michael Farrell - Beaumont Hospital
Jane Cryan - Beaumont Hospital
Darach Crimmins - Temple University
John Caird - Temple University
Jane Pears - Boston Children's Hospital
Michelle Monje - Stanford University
Marie-Anne Debily - Institut Gustave Roussy
David Castel - Institut Gustave Roussy
Jacques Grill - Institut Gustave Roussy
Cynthia Hawkins - Hospital for Sick Children
Hamid Nikbakht - McGill University
Nada Jabado - Children's Hospital of Philadelphia
Suzanne J. Baker - St. Jude Children's Research Hospital
Stefan M. Pfister - German Cancer Research Center
David T.W. Jones - Montreal Neurological Institute and Hospital
Maryam Fouladi - Cincinnati Children's Hospital Medical Center
André O. von Bueren - University of Göttingen
Michael Baudis - SIB Swiss Institute of Bioinformatics
Adam Resnick - Children's Hospital of Philadelphia
Chris Jones - Institute of Cancer Research
Publication Details: Cancer cell, Vol.32(4), pp.520-537.e5
Publisher: Elsevier Inc
Identifiers: 9919281208331
Academic Unit: Northern Borders University
Language: English
Resource Type: Journal article