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      Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations.

      1 , 2 , 3 , 1 , 4 , 2 , 1 , 3 , 5 , 5 , 6 , 7 , 3 , 8 , 9 , 10 , 10 , 2 , 11 , 11 , 12 , 13 , 2 , 14 , 15 , 16 , 17 , 1 , 1 , 1 , 1 , 18 , 18 , 1 , 19 , 20 , 1 , 21 , 22 , 20 , 21 , 11 , 1 , 23 , 1 , 2
      Nature genetics

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          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.

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          Most cited references19

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          Recent advances in neuroblastoma.

          John Maris (2010)
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            The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report.

            Because current approaches to risk classification and treatment stratification for children with neuroblastoma (NB) vary greatly throughout the world, it is difficult to directly compare risk-based clinical trials. The International Neuroblastoma Risk Group (INRG) classification system was developed to establish a consensus approach for pretreatment risk stratification. The statistical and clinical significance of 13 potential prognostic factors were analyzed in a cohort of 8,800 children diagnosed with NB between 1990 and 2002 from North America and Australia (Children's Oncology Group), Europe (International Society of Pediatric Oncology Europe Neuroblastoma Group and German Pediatric Oncology and Hematology Group), and Japan. Survival tree regression analyses using event-free survival (EFS) as the primary end point were performed to test the prognostic significance of the 13 factors. Stage, age, histologic category, grade of tumor differentiation, the status of the MYCN oncogene, chromosome 11q status, and DNA ploidy were the most highly statistically significant and clinically relevant factors. A new staging system (INRG Staging System) based on clinical criteria and tumor imaging was developed for the INRG Classification System. The optimal age cutoff was determined to be between 15 and 19 months, and 18 months was selected for the classification system. Sixteen pretreatment groups were defined on the basis of clinical criteria and statistically significantly different EFS of the cohort stratified by the INRG criteria. Patients with 5-year EFS more than 85%, more than 75% to or = 50% to < or = 75%, or less than 50% were classified as very low risk, low risk, intermediate risk, or high risk, respectively. By defining homogenous pretreatment patient cohorts, the INRG classification system will greatly facilitate the comparison of risk-based clinical trials conducted in different regions of the world and the development of international collaborative studies.
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              Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes.

              Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour. Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%). Here we present a whole-genome sequence analysis of 87 neuroblastoma of all stages. Few recurrent amino-acid-changing mutations were found. In contrast, analysis of structural defects identified a local shredding of chromosomes, known as chromothripsis, in 18% of high-stage neuroblastoma. These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization. In addition, ATRX, TIAM1 and a series of regulators of the Rac/Rho pathway were mutated, further implicating defects in neuritogenesis in neuroblastoma. Most tumours with defects in these genes were aggressive high-stage neuroblastomas, but did not carry MYCN amplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromothripsis and neuritogenesis gene alterations, which frequently occur in high-risk tumours.
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                Author and article information

                Journal
                Nat. Genet.
                Nature genetics
                1546-1718
                1061-4036
                Aug 2015
                : 47
                : 8
                Affiliations
                [1 ] Department of Oncogenomics, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.
                [2 ] 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.
                [3 ] ICGEX Platform, Institut Curie, Paris, France.
                [4 ] 1] ICGEX Platform, Institut Curie, Paris, France. [2] Laboratory RTOP (Recherche Translationelle en Oncologie Pédiatrique), Transfer Department, Institut Curie, Paris, France.
                [5 ] Laboratory RTOP (Recherche Translationelle en Oncologie Pédiatrique), Transfer Department, Institut Curie, Paris, France.
                [6 ] Unité de Génétique Somatique, Institut Curie, Paris, France.
                [7 ] Centre Léon-Bérard, Laboratoire de Recherche Translationnelle Lyon, Lyon, France.
                [8 ] Département de Pédiatrie, Institut Curie, Paris, France.
                [9 ] Princess Margaret Cancer Centre, University Health Network; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
                [10 ] 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.
                [11 ] Pediatric Oncology Branch, Oncogenomics Section, Center for Cancer Research, US National Institutes of Health, Gaithersburg, Maryland, USA.
                [12 ] Department of Biostatistics, University of Florida, Children's Oncology Group (COG), Gainesville, Florida, USA.
                [13 ] 1] The Ohio State University College of Medicine, Columbus, Ohio, USA. [2] Biopathology Center, Nationwide Children's Hospital, Columbus, Ohio, USA.
                [14 ] 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.
                [15 ] Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA.
                [16 ] Office of Cancer Genomics, National Cancer Institute, Bethesda, Maryland, USA.
                [17 ] Translational Cancer Therapeutics Laboratory, Cancer Research UK, London, UK.
                [18 ] 1] Department of Experimental Immunohematology, Sanquin Research, Amsterdam, the Netherlands. [2] Landsteiner Laboratory, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.
                [19 ] 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.
                [20 ] Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.
                [21 ] INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Institut Curie, Paris, France.
                [22 ] Biopathology Center, Nationwide Children's Hospital, Columbus, Ohio, USA.
                [23 ] 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.
                Article
                ng.3333 NIHMS757254
                10.1038/ng.3333
                26121087
                d0b84098-10ee-4244-8320-44311dd13703
                History

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