1. Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations.
- Author
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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 TB, Zwijnenburg DA, Ebus ME, van Sluis P, Hakkert A, van Wezel E, van der Schoot CE, Westerhout EM, Schulte JH, Tytgat GA, Dolman ME, Janoueix-Lerosey I, Gerhard DS, Caron HN, Delattre O, Khan J, Versteeg R, Schleiermacher G, Molenaar JJ, and Maris JM
- Subjects
- 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, Male, Mice, SCID, Mitogen-Activated Protein Kinases metabolism, Neuroblastoma drug therapy, 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 metabolism, MAP Kinase Signaling System genetics, Mitogen-Activated Protein Kinases genetics, Mutation, Neoplasm Recurrence, Local genetics, Neuroblastoma genetics, ras Proteins genetics
- 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.
- Published
- 2015
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