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Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations.
- 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