Journal
NATURE GENETICS
Volume 47, Issue 8, Pages 864-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3333
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Funding
- US National Institutes of Health [RC1MD004418, HHSN261200800001E]
- University of Pennsylvania Genome Frontiers Institute
- National Cancer Institute
- Annenberg Foundation
- Nelia and Amadeo Barletta Foundation
- SiRIC/INCa [INCa-DGOS-4654]
- Comite d'Evaluation et Suivi des Projets de Recherche de Transfert (CEST) of Institut Curie
- Associations Enfants et Sante
- Association Hubert Gouin Enfance et Cancer
- Les Bagouz a Manon
- Les Amis de Claire
- EQUIPEX Investissements d'Avenir program [ANR-10-EQPX-03]
- Agence Nationale de le Recherche [ANR10-INBS-09-08]
- Canceropole Ile-de-France
- Villa Joep Foundation
- Kinderen Kankervrij Foundation
- Netherlands Cancer Foundation
- NATIONAL CANCER INSTITUTE [U10CA098413, U10CA180886, F30CA192831, U10CA098543] Funding Source: NIH RePORTER
- NATIONAL CENTER ON MINORITY HEALTH AND HEALTH DISPARITIES [RC1MD004418] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [T32HG000046] Funding Source: NIH RePORTER
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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.
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