| Literature DB >> 26121087 |
Thomas F Eleveld1, Derek A Oldridge2, Virginie Bernard3, Jan Koster1, Léo Colmet Daage4, Sharon J Diskin2, Linda Schild1, Nadia Bessoltane Bentahar3, Angela Bellini5, Mathieu Chicard5, Eve Lapouble6, Valérie Combaret7, Patricia Legoix-Né3, Jean Michon8, Trevor J Pugh9, Lori S Hart10, JulieAnn Rader10, Edward F Attiyeh2, Jun S Wei11, Shile Zhang11, Arlene Naranjo12, Julie M Gastier-Foster13, Michael D Hogarty2, Shahab Asgharzadeh14, Malcolm A Smith15, Jaime M Guidry Auvil16, Thomas B K Watkins17, Danny A Zwijnenburg1, Marli E Ebus1, Peter van Sluis1, Anne Hakkert1, Esther van Wezel18, C Ellen van der Schoot18, Ellen M Westerhout1, Johannes H Schulte19, Godelieve A Tytgat20, M Emmy M Dolman1, Isabelle Janoueix-Lerosey21, Daniela S Gerhard22, Huib N Caron20, Olivier Delattre21, Javed Khan11, Rogier Versteeg1, Gudrun Schleiermacher23, Jan J Molenaar1, John M Maris2.
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.Entities:
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Year: 2015 PMID： 26121087 PMCID： PMC4775079 DOI： 10.1038/ng.3333
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330