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Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations.

Authors :
Eleveld, Thomas F
Koster, Jan
Schild, Linda
Zwijnenburg, Danny A
Ebus, Marli E
van Sluis, Peter
Hakkert, Anne
Westerhout, Ellen M
Dolman, M Emmy M
Versteeg, Rogier
Molenaar, Jan J
Hart, Lori S
Rader, JulieAnn
Wei, Jun S
Zhang, Shile
Khan, Javed
Naranjo, Arlene
Gastier-Foster, Julie M
Asgharzadeh, Shahab
Smith, Malcolm A
Source :
Nature Genetics; Aug2015, Vol. 47 Issue 8, p864-871, 8p, 2 Charts, 3 Graphs
Publication Year :
2015

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
10614036
Volume :
47
Issue :
8
Database :
Complementary Index
Journal :
Nature Genetics
Publication Type :
Academic Journal
Accession number :
108592398
Full Text :
https://doi.org/10.1038/ng.3333