Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations

Thomas F. Eleveld; Derek A. Oldridge; Virginie Bernard; Jan Koster; Leo 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, Leo 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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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)	864-871
Number of pages	8
Journal	Nature Genetics
Volume	47
Issue number	8
DOIs	https://doi.org/10.1038/ng.3333
Publication status	Published - 30 Aug 2015
Externally published	Yes

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Eleveld, T. F., Oldridge, D. A., Bernard, V., Koster, J., Daage, L. C., 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), 864-871. https://doi.org/10.1038/ng.3333

@article{3e310cda820f488e8f6c184812fda676,

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.",

author = "Eleveld, {Thomas F.} and Oldridge, {Derek A.} and Virginie Bernard and Jan Koster and Daage, {Leo Colmet} 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,

day = "30",

doi = "10.1038/ng.3333",

language = "English",

volume = "47",

pages = "864--871",

journal = "Nature Genetics",

issn = "1061-4036",

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Eleveld, TF, Oldridge, DA, Bernard, V, Koster, J, Daage, LC, 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. 864-871. 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 - Daage, Leo Colmet

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 - 2015/8/30

Y1 - 2015/8/30

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.

UR - https://www.mendeley.com/catalogue/efc12663-0138-3738-90df-b4f7b413541b/

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

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