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

Research output: Contribution to journalArticlepeer-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 languageEnglish
Pages (from-to)864-871
Number of pages8
JournalNature Genetics
Volume47
Issue number8
DOIs
Publication statusPublished - 30 Aug 2015

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