title: Spatial heterogeneity in medulloblastoma.
abstract: Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.
authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: A Sorana
authors.initials: AS
authors.lastname: Morrissy
authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Florence M G
authors.initials: FMG
authors.lastname: Cavalli
authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.|Department of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.|Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Düsseldorf, Germany.
authors.forename: Marc
authors.identifier: http://orcid.org/0000-0002-9404-9993
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authors.lastname: Remke
authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Vijay
authors.identifier: http://orcid.org/0000-0002-6557-895X
authors.initials: V
authors.lastname: Ramaswamy
authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David J H
authors.initials: DJH
authors.lastname: Shih
authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Borja L
authors.initials: BL
authors.lastname: Holgado
authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Hamza
authors.initials: H
authors.lastname: Farooq
authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Donovan
authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Cancer Research Program, McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
authors.forename: Livia
authors.initials: L
authors.lastname: Garzia
authors.affiliation: MacFeeters-Hamilton Brain Tumour Centre, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Sameer
authors.initials: S
authors.lastname: Agnihotri
authors.affiliation: Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.initials: EN
authors.lastname: Kiehna
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Eloi
authors.initials: E
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Chelsea
authors.initials: C
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authors.affiliation: Departments of Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Simon
authors.identifier: http://orcid.org/0000-0002-0372-2266
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authors.lastname: Papillon-Cavanagh
authors.affiliation: Departments of Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Hamid
authors.initials: H
authors.lastname: Nikbakht
authors.affiliation: Departments of Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Tenzin
authors.initials: T
authors.lastname: Gayden
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jonathon
authors.initials: J
authors.lastname: Torchia
authors.affiliation: Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.|Department of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.|Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Düsseldorf, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Picard
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Diana M
authors.identifier: http://orcid.org/0000-0002-6173-6957
authors.initials: DM
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.initials: M
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.initials: B
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Xiaochong
authors.initials: X
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Cancer Research UK London Research Institute, London, UK.
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Yuan Yao
authors.initials: YY
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authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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authors.initials: PA
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authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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authors.initials: DTW
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
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authors.initials: J
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Xin
authors.identifier: http://orcid.org/0000-0001-6292-3087
authors.initials: X
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authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen C
authors.initials: SC
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authors.affiliation: Informatics and Biocomputing, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jüri
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authors.affiliation: Department of Pathology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
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authors.affiliation: Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.initials: HI
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.initials: U
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authors.affiliation: Division of Pediatric Oncology, Children's National Medical Center, Washington, DC, USA.
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authors.initials: BR
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authors.affiliation: Division of Pediatric Neuro-Surgery, Children's National Medical Center, Washington, DC, USA.
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authors.affiliation: Department of Neurology, Children's National Medical Center, Washington, DC, USA.
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authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
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authors.initials: P
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authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, University Hospital Heidelberg, Heidelberg, Germany.
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authors.initials: SM
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authors.initials: U
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authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.initials: P
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authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.initials: A
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authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.initials: E
authors.lastname: Bouffet
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.|Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.initials: JT
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authors.affiliation: The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
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authors.identifier: http://orcid.org/0000-0003-0185-8861
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authors.initials: C
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.initials: Y
authors.lastname: Ma
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.initials: RA
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
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authors.identifier: http://orcid.org/0000-0002-0905-2742
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authors.affiliation: Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
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authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Molecular Biology &Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Steven J M
authors.initials: SJM
authors.lastname: Jones
authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Neurosurgery, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sunit
authors.identifier: http://orcid.org/0000-0002-2146-4168
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authors.affiliation: Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.affiliation: Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D055106:Genome-Wide Association Study; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome