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.

• Authors: Thomas F Eleveld, Derek A Oldridge, Virginie Bernard, Jan Koster, Léo 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
• Journal: Nature genetics (Nat Genet) Vol. 47 Issue 8 Pg. 864-71 (08 2015) ISSN: 1546-1718 [Electronic] United States
• PMID: 26121087 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzimidazoles
• Cyclin-Dependent Kinase Inhibitor p16
• binimetinib
• Anaplastic Lymphoma Kinase
• Receptor Protein-Tyrosine Kinases
• Mitogen-Activated Protein Kinases
• ras Proteins

Topics

• Anaplastic Lymphoma Kinase
• Animals
• Benzimidazoles (pharmacology)
• Blotting, Western
• Cell Line, Tumor
• Child
• Child, Preschool
• Chromosome Aberrations
• Cyclin-Dependent Kinase Inhibitor p16 (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Humans
• Infant
• MAP Kinase Signaling System (genetics)
• Male
• Mice, SCID
• Mitogen-Activated Protein Kinases (genetics, metabolism)
• Mutation
• Neoplasm Recurrence, Local (genetics)
• Neuroblastoma (drug therapy, genetics, pathology)
• Phosphorylation (drug effects)
• Receptor Protein-Tyrosine Kinases (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Xenograft Model Antitumor Assays
• ras Proteins (genetics, metabolism)