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Nat Genet. 2015 Aug;47(8):864-71. doi: 10.1038/ng.3333. Epub 2015 Jun 29.

Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations.

Author information

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.

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.

PMID:
26121087
PMCID:
PMC4775079
DOI:
10.1038/ng.3333
[Indexed for MEDLINE]
Free PMC Article

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