Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations.

Autor: Eleveld TF; Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands., Oldridge DA; 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., Bernard V; ICGEX Platform, Institut Curie, Paris, France., Koster J; Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands., Colmet Daage L; 1] ICGEX Platform, Institut Curie, Paris, France. [2] Laboratory RTOP (Recherche Translationelle en Oncologie Pédiatrique), Transfer Department, Institut Curie, Paris, France., Diskin SJ; 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., Schild L; Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands., Bentahar NB; ICGEX Platform, Institut Curie, Paris, France., Bellini A; Laboratory RTOP (Recherche Translationelle en Oncologie Pédiatrique), Transfer Department, Institut Curie, Paris, France., Chicard M; Laboratory RTOP (Recherche Translationelle en Oncologie Pédiatrique), Transfer Department, Institut Curie, Paris, France., Lapouble E; Unité de Génétique Somatique, Institut Curie, Paris, France., Combaret V; Centre Léon-Bérard, Laboratoire de Recherche Translationnelle Lyon, Lyon, France., Legoix-Né P; ICGEX Platform, Institut Curie, Paris, France., Michon J; Département de Pédiatrie, Institut Curie, Paris, France., Pugh TJ; Princess Margaret Cancer Centre, University Health Network; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada., Hart LS; 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., Rader J; 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., Attiyeh EF; 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., Wei JS; Pediatric Oncology Branch, Oncogenomics Section, Center for Cancer Research, US National Institutes of Health, Gaithersburg, Maryland, USA., Zhang S; Pediatric Oncology Branch, Oncogenomics Section, Center for Cancer Research, US National Institutes of Health, Gaithersburg, Maryland, USA., Naranjo A; Department of Biostatistics, University of Florida, Children's Oncology Group (COG), Gainesville, Florida, USA., Gastier-Foster JM; 1] The Ohio State University College of Medicine, Columbus, Ohio, USA. [2] Biopathology Center, Nationwide Children's Hospital, Columbus, Ohio, USA., Hogarty MD; 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., Asgharzadeh S; 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., Smith MA; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA., Guidry Auvil JM; Office of Cancer Genomics, National Cancer Institute, Bethesda, Maryland, USA., Watkins TB; Translational Cancer Therapeutics Laboratory, Cancer Research UK, London, UK., Zwijnenburg DA; Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands., Ebus ME; Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands., van Sluis P; Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands., Hakkert A; Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands., van Wezel E; 1] Department of Experimental Immunohematology, Sanquin Research, Amsterdam, the Netherlands. [2] Landsteiner Laboratory, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands., van der Schoot CE; 1] Department of Experimental Immunohematology, Sanquin Research, Amsterdam, the Netherlands. [2] Landsteiner Laboratory, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands., Westerhout EM; Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands., Schulte JH; 1] Department of Pediatric Oncology and Hematology, Charité University Medicine, Berlin, Germany. [2] German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany. [3] Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany. [4] Translational Neuro-Oncology, West German Cancer Center (WTZ), University Hospital Essen, Essen, Germany., Tytgat GA; Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands., Dolman ME; Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands., Janoueix-Lerosey I; INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Institut Curie, Paris, France., Gerhard DS; Biopathology Center, Nationwide Children's Hospital, Columbus, Ohio, USA., Caron HN; Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands., Delattre O; INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Institut Curie, Paris, France., Khan J; Pediatric Oncology Branch, Oncogenomics Section, Center for Cancer Research, US National Institutes of Health, Gaithersburg, Maryland, USA., Versteeg R; Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands., Schleiermacher G; 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., Molenaar JJ; Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands., Maris JM; 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.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2015 Aug; Vol. 47 (8), pp. 864-71. Date of Electronic Publication: 2015 Jun 29.
DOI: 10.1038/ng.3333
Abstrakt: 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.
Databáze: MEDLINE