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 ZhangArlene 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

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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

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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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