title: Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations.
abstract: The majority of patients with neuroblastoma have tumors that initially respond to chemotherapy, but a large proportion will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole-genome sequencing of 23 paired diagnostic and relapse neuroblastomas showed clonal evolution from the diagnostic tumor, with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed mutations predicted to activate the RAS-MAPK pathway. Seven of these events were detected only in the relapse tumor, whereas the others showed clonal enrichment. In neuroblastoma cell lines, we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18; 61%), and these lesions predicted sensitivity to MEK inhibition in vitro and in vivo. Our findings provide a rationale for genetic characterization of relapse neuroblastomas and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease.
authors.affiliation: Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Eleveld
authors.affiliation: 1] Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [2] Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [3] Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Oldridge
authors.affiliation: ICGEX Platform, Institut Curie, Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Bernard
authors.affiliation: Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jan
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authors.lastname: Koster
authors.affiliation: 1] ICGEX Platform, Institut Curie, Paris, France. [2] Laboratory RTOP (Recherche Translationelle en Oncologie Pédiatrique), Transfer Department, Institut Curie, Paris, France.
authors.forename: Léo
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authors.lastname: Colmet Daage
authors.affiliation: 1] Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [2] Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [3] Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Diskin
authors.affiliation: Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Linda
authors.initials: L
authors.lastname: Schild
authors.affiliation: ICGEX Platform, Institut Curie, Paris, France.
authors.forename: Nadia Bessoltane
authors.initials: NB
authors.lastname: Bentahar
authors.affiliation: Laboratory RTOP (Recherche Translationelle en Oncologie Pédiatrique), Transfer Department, Institut Curie, Paris, France.
authors.forename: Angela
authors.initials: A
authors.lastname: Bellini
authors.affiliation: Laboratory RTOP (Recherche Translationelle en Oncologie Pédiatrique), Transfer Department, Institut Curie, Paris, France.
authors.forename: Mathieu
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authors.lastname: Chicard
authors.affiliation: Unité de Génétique Somatique, Institut Curie, Paris, France.
authors.forename: Eve
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authors.lastname: Lapouble
authors.affiliation: Centre Léon-Bérard, Laboratoire de Recherche Translationnelle Lyon, Lyon, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Combaret
authors.affiliation: ICGEX Platform, Institut Curie, Paris, France.
authors.forename: Patricia
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authors.lastname: Legoix-Né
authors.affiliation: Département de Pédiatrie, Institut Curie, Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Michon
authors.affiliation: Princess Margaret Cancer Centre, University Health Network; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Trevor J
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authors.lastname: Pugh
authors.affiliation: 1] Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [2] Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Lori S
authors.initials: LS
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authors.affiliation: 1] Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [2] Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
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authors.affiliation: 1] Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [2] Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [3] Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Edward F
authors.initials: EF
authors.lastname: Attiyeh
authors.affiliation: Pediatric Oncology Branch, Oncogenomics Section, Center for Cancer Research, US National Institutes of Health, Gaithersburg, Maryland, USA.
authors.forename: Jun S
authors.initials: JS
authors.lastname: Wei
authors.affiliation: Pediatric Oncology Branch, Oncogenomics Section, Center for Cancer Research, US National Institutes of Health, Gaithersburg, Maryland, USA.
authors.forename: Shile
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authors.lastname: Zhang
authors.affiliation: Department of Biostatistics, University of Florida, Children's Oncology Group (COG), Gainesville, Florida, USA.
authors.forename: Arlene
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authors.lastname: Naranjo
authors.affiliation: 1] The Ohio State University College of Medicine, Columbus, Ohio, USA. [2] Biopathology Center, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Julie M
authors.initials: JM
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authors.affiliation: 1] Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [2] Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [3] Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hogarty
authors.affiliation: 1] Division of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California, USA. [2] Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA. [3] Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Shahab
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authors.lastname: Asgharzadeh
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Office of Cancer Genomics, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Jaime M
authors.initials: JM
authors.lastname: Guidry Auvil
authors.affiliation: Translational Cancer Therapeutics Laboratory, Cancer Research UK, London, UK.
authors.forename: Thomas B K
authors.initials: TB
authors.lastname: Watkins
authors.affiliation: Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Danny A
authors.initials: DA
authors.lastname: Zwijnenburg
authors.affiliation: Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Marli E
authors.initials: ME
authors.lastname: Ebus
authors.affiliation: Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: van Sluis
authors.affiliation: Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Anne
authors.initials: A
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authors.affiliation: 1] Department of Experimental Immunohematology, Sanquin Research, Amsterdam, the Netherlands. [2] Landsteiner Laboratory, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: van Wezel
authors.affiliation: 1] Department of Experimental Immunohematology, Sanquin Research, Amsterdam, the Netherlands. [2] Landsteiner Laboratory, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: C Ellen
authors.initials: CE
authors.lastname: van der Schoot
authors.affiliation: Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.
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authors.initials: EM
authors.lastname: Westerhout
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authors.forename: Johannes H
authors.initials: JH
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authors.affiliation: Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Godelieve A
authors.initials: GA
authors.lastname: Tytgat
authors.affiliation: Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: M Emmy M
authors.initials: ME
authors.lastname: Dolman
authors.affiliation: INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Institut Curie, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Janoueix-Lerosey
authors.affiliation: Biopathology Center, Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Daniela S
authors.initials: DS
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authors.affiliation: Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Huib N
authors.initials: HN
authors.lastname: Caron
authors.affiliation: INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Institut Curie, Paris, France.
authors.forename: Olivier
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authors.affiliation: Pediatric Oncology Branch, Oncogenomics Section, Center for Cancer Research, US National Institutes of Health, Gaithersburg, Maryland, USA.
authors.forename: Javed
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authors.lastname: Khan
authors.affiliation: Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
authors.affiliation: 1] Laboratory RTOP (Recherche Translationelle en Oncologie Pédiatrique), Transfer Department, Institut Curie, Paris, France. [2] Département de Pédiatrie, Institut Curie, Paris, France. [3] INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Institut Curie, Paris, France.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schleiermacher
authors.affiliation: Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Molenaar
authors.affiliation: 1] Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [2] Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [3] Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D019941:Cyclin-Dependent Kinase Inhibitor p16; C581313:binimetinib; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins