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

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

Science

Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Pennsylvania Hospital
ICGEX Platform
Institut Curie
Laboratory RTOP (Recherche Translationelle en Oncologie Pédiatrique)
Unité de Génétique Somatique
Centre Léon Bérard
Département de Pédiatrie
Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada
National Cancer Institute United States
Utrecht University, University of Florida
Ohio University
Department of Biological Sciences, University of Southern California, Los Angeles, California, USA
National Cancer Institute Thailand
Translational Cancer Therapeutics Laboratory
STI Outpatient Clinic, Public Health Service of Amsterdam (GGD Amsterdam), Amsterdam, The Netherlands.
Institute for Transfusion Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Academic Medical Center
Laboratoire de Génétique et Biologie des Cancers
Biopathology Center
Transfer Department

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	864-71
Number of pages	8
Journal	Nature Genetics
Volume	47
Issue number	8
DOIs	https://doi.org/10.1038/ng.3333
Publication status	Published - Aug 2015

Keywords

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

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10.1038/ng.3333

Cite this

Eleveld, T. F., Oldridge, D. A., Bernard, V., Koster, J., Colmet Daage, L., Diskin, S. J., Schild, L., Bentahar, N. B., Bellini, A., Chicard, M., Lapouble, E., Combaret, V., Legoix-Né, P., Michon, J., Pugh, T. J., Hart, L. S., Rader, J., Attiyeh, E. F., Wei, J. S., ... Maris, J. M. (2015). Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nature Genetics, 47(8), 864-71. https://doi.org/10.1038/ng.3333

@article{5700dda39d7d46cdb8ad3f17aa193def,

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.",

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

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

year = "2015",

month = aug,

doi = "10.1038/ng.3333",

language = "English",

volume = "47",

pages = "864--71",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "8",

}

Eleveld, TF, Oldridge, DA, Bernard, V, Koster, J, Colmet Daage, L, Diskin, SJ, Schild, L, Bentahar, NB, Bellini, A, Chicard, M, Lapouble, E, Combaret, V, Legoix-Né, P, Michon, J, Pugh, TJ, Hart, LS, Rader, J, Attiyeh, EF, Wei, JS, Zhang, S, Naranjo, A, Gastier-Foster, JM, Hogarty, MD, Asgharzadeh, S, Smith, MA, Guidry Auvil, JM, Watkins, TBK, Zwijnenburg, DA, Ebus, ME, van Sluis, P, Hakkert, A, van Wezel, E, van der Schoot, CE, Westerhout, EM, Schulte, JH, Tytgat, GA, Dolman, MEM, Janoueix-Lerosey, I, Gerhard, DS, Caron, HN, Delattre, O, Khan, J, Versteeg, R, Schleiermacher, G, Molenaar, JJ & Maris, JM 2015, 'Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations', Nature Genetics, vol. 47, no. 8, pp. 864-71. https://doi.org/10.1038/ng.3333

TY - JOUR

T1 - Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations

AU - Eleveld, Thomas F

AU - Oldridge, Derek A

AU - Bernard, Virginie

AU - Koster, Jan

AU - Colmet Daage, Léo

AU - Diskin, Sharon J

AU - Schild, Linda

AU - Bentahar, Nadia Bessoltane

AU - Bellini, Angela

AU - Chicard, Mathieu

AU - Lapouble, Eve

AU - Combaret, Valérie

AU - Legoix-Né, Patricia

AU - Michon, Jean

AU - Pugh, Trevor J

AU - Hart, Lori S

AU - Rader, JulieAnn

AU - Attiyeh, Edward F

AU - Wei, Jun S

AU - Zhang, Shile

AU - Naranjo, Arlene

AU - Gastier-Foster, Julie M

AU - Hogarty, Michael D

AU - Asgharzadeh, Shahab

AU - Smith, Malcolm A

AU - Guidry Auvil, Jaime M

AU - Watkins, Thomas B K

AU - Zwijnenburg, Danny A

AU - Ebus, Marli E

AU - van Sluis, Peter

AU - Hakkert, Anne

AU - van Wezel, Esther

AU - van der Schoot, C Ellen

AU - Westerhout, Ellen M

AU - Schulte, Johannes H

AU - Tytgat, Godelieve A

AU - Dolman, M Emmy M

AU - Janoueix-Lerosey, Isabelle

AU - Gerhard, Daniela S

AU - Caron, Huib N

AU - Delattre, Olivier

AU - Khan, Javed

AU - Versteeg, Rogier

AU - Schleiermacher, Gudrun

AU - Molenaar, Jan J

AU - Maris, John M

PY - 2015/8

Y1 - 2015/8

N2 - 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.

AB - 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.

KW - Anaplastic Lymphoma Kinase

KW - Animals

KW - Benzimidazoles/pharmacology

KW - Blotting, Western

KW - Cell Line, Tumor

KW - Child

KW - Child, Preschool

KW - Chromosome Aberrations

KW - Cyclin-Dependent Kinase Inhibitor p16/genetics

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - HEK293 Cells

KW - Humans

KW - Infant

KW - MAP Kinase Signaling System/genetics

KW - Male

KW - Mice, SCID

KW - Mitogen-Activated Protein Kinases/genetics

KW - Mutation

KW - Neoplasm Recurrence, Local/genetics

KW - Neuroblastoma/drug therapy

KW - Phosphorylation/drug effects

KW - Receptor Protein-Tyrosine Kinases/genetics

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Xenograft Model Antitumor Assays

KW - ras Proteins/genetics

U2 - 10.1038/ng.3333

DO - 10.1038/ng.3333

M3 - Article

C2 - 26121087

SN - 1061-4036

VL - 47

SP - 864

EP - 871

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations

Abstract

Keywords

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