Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations
| Autor: | Jean Michon, Gudrun Schleiermacher, Malcolm A. Smith, JulieAnn Rader, Trevor J. Pugh, Patricia Legoix-Né, Jan Koster, Daniela S Gerhard, Edward F. Attiyeh, Olivier Delattre, Shahab Asgharzadeh, Julie M. Gastier-Foster, Sharon J. Diskin, Jan J. Molenaar, Leo Colmet Daage, Rogier Versteeg, Esther M. van Wezel, Eve Lapouble, Marli E. Ebus, Godelieve A.M. Tytgat, Javed Khan, Ellen M. Westerhout, Mathieu Chicard, Lori S. Hart, Nadia Bessoltane Bentahar, M. Emmy M. Dolman, Linda Schild, Anne Hakkert, Virginie Bernard, Valérie Combaret, Johannes H. Schulte, Angela Bellini, Jaime M. Guidry Auvil, Jun S. Wei, Thomas B.K. Watkins, Michael D. Hogarty, Shile Zhang, Thomas F. Eleveld, John M. Maris, Derek A. Oldridge, Huib N. Caron, Peter van Sluis, Isabelle Janoueix-Lerosey, Arlene Naranjo, C. Ellen van der Schoot, Danny A. Zwijnenburg |
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| Přispěvatelé: | Graduate School, Oncogenomics, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA -Cancer Center Amsterdam, Paediatric Oncology, Landsteiner Laboratory, Clinical Haematology, APH - Amsterdam Public Health, Human Genetics, Oncology |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Somatic cell MAP Kinase Signaling System medicine.medical_treatment Blotting Western Medizin Mice SCID Biology medicine.disease_cause Somatic evolution in cancer Article Neuroblastoma In vivo Cell Line Tumor Genetics medicine Anaplastic lymphoma kinase Animals Humans Anaplastic Lymphoma Kinase Phosphorylation Child Cyclin-Dependent Kinase Inhibitor p16 Chromosome Aberrations Mutation Chemotherapy Reverse Transcriptase Polymerase Chain Reaction Infant Receptor Protein-Tyrosine Kinases medicine.disease Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic HEK293 Cells Child Preschool Immunology Cancer research ras Proteins Biomarker (medicine) Benzimidazoles Female Mitogen-Activated Protein Kinases Neoplasm Recurrence Local |
| Zdroj: | Nature genetics, 47(8), 864-871. Nature Publishing Group |
| ISSN: | 1061-4036 |
| Popis: | The majority of neuroblastoma patients have tumors that initially respond to chemotherapy, but a large proportion of patients will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole genome sequencing of 23 paired diagnostic and relapsed 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 signaling pathway. Seven events were detected only in the relapse tumor while 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 for sensitivity to MEK inhibition in vitro and in vivo. Our findings provide the rationale for genetic characterization of relapse neuroblastoma and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease. |
| Databáze: | OpenAIRE |
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