Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations

Thomas F Eleveld; Derek A Oldridge; Virginie Bernard; Jan Koster; Léo Colmet Daage; Sharon J Diskin; Linda Schild; Nadia Bessoltane Bentahar; Angela Bellini; Mathieu Chicard; Eve Lapouble; Valérie Combaret; Patricia Legoix-Né; Jean Michon; Trevor J Pugh; Lori S Hart; JulieAnn Rader; Edward F Attiyeh; Jun S Wei; Shile Zhang; Arlene Naranjo; Julie M Gastier-Foster; Michael D Hogarty; Shahab Asgharzadeh; Malcolm A Smith; Jaime M Guidry Auvil; Thomas B K Watkins; Danny A Zwijnenburg; Marli E Ebus; Peter van Sluis; Anne Hakkert; Esther van Wezel; C Ellen van der Schoot; Ellen M Westerhout; Johannes H Schulte; Godelieve A Tytgat; M Emmy M Dolman; Isabelle Janoueix-Lerosey; Daniela S Gerhard; Huib N Caron; Olivier Delattre; Javed Khan; Rogier Versteeg; Gudrun Schleiermacher; Jan J Molenaar; John M Maris

doi:10.1038/ng.3333

Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations

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

Authors

Thomas F Eleveld¹, Derek A Oldridge², Virginie Bernard³, Jan Koster¹, Léo Colmet Daage⁴, Sharon J Diskin², Linda Schild¹, Nadia Bessoltane Bentahar³, Angela Bellini⁵, Mathieu Chicard⁵, Eve Lapouble⁶, Valérie Combaret⁷, Patricia Legoix-Né³, Jean Michon⁸, Trevor J Pugh⁹, Lori S Hart¹⁰, JulieAnn Rader¹⁰, Edward F Attiyeh², Jun S Wei¹¹, Shile Zhang¹¹, Arlene Naranjo¹², Julie M Gastier-Foster¹³, Michael D Hogarty², Shahab Asgharzadeh¹⁴, Malcolm A Smith¹⁵, Jaime M Guidry Auvil¹⁶, Thomas B K Watkins¹⁷, Danny A Zwijnenburg¹, Marli E Ebus¹, Peter van Sluis¹, Anne Hakkert¹, Esther van Wezel¹⁸, C Ellen van der Schoot¹⁸, Ellen M Westerhout¹, Johannes H Schulte¹⁹, Godelieve A Tytgat²⁰, M Emmy M Dolman¹, Isabelle Janoueix-Lerosey²¹, Daniela S Gerhard²², Huib N Caron²⁰, Olivier Delattre²¹, Javed Khan¹¹, Rogier Versteeg¹, Gudrun Schleiermacher²³, Jan J Molenaar¹, John M Maris²

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.

PMID: 26121087
PMCID: PMC4775079
DOI: 10.1038/ng.3333

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Anaplastic Lymphoma Kinase
Animals
Benzimidazoles / pharmacology
Blotting, Western
Cell Line, Tumor
Child
Child, Preschool
Chromosome Aberrations
Cyclin-Dependent Kinase Inhibitor p16 / genetics
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
Female
Gene Expression Regulation, Neoplastic
HEK293 Cells
Humans
Infant
MAP Kinase Signaling System / genetics*
Male
Mice, SCID
Mitogen-Activated Protein Kinases / genetics*
Mitogen-Activated Protein Kinases / metabolism
Mutation*
Neoplasm Recurrence, Local / genetics*
Neuroblastoma / drug therapy
Neuroblastoma / genetics*
Neuroblastoma / pathology
Phosphorylation / drug effects
Receptor Protein-Tyrosine Kinases / genetics
Receptor Protein-Tyrosine Kinases / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Xenograft Model Antitumor Assays
ras Proteins / genetics*
ras Proteins / metabolism

Substances

Benzimidazoles
Cyclin-Dependent Kinase Inhibitor p16
binimetinib
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases
Mitogen-Activated Protein Kinases
ras Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding