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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.

SUBMITTER: Eleveld TF 

PROVIDER: S-EPMC4775079 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations.

Eleveld Thomas F TF   Oldridge Derek A DA   Bernard Virginie V   Koster Jan J   Colmet Daage Léo L   Diskin Sharon J SJ   Schild Linda L   Bentahar Nadia Bessoltane NB   Bellini Angela A   Chicard Mathieu M   Lapouble Eve E   Combaret Valérie V   Legoix-Né Patricia P   Michon Jean J   Pugh Trevor J TJ   Hart Lori S LS   Rader JulieAnn J   Attiyeh Edward F EF   Wei Jun S JS   Zhang Shile S   Naranjo Arlene A   Gastier-Foster Julie M JM   Hogarty Michael D MD   Asgharzadeh Shahab S   Smith Malcolm A MA   Guidry Auvil Jaime M JM   Watkins Thomas B K TB   Zwijnenburg Danny A DA   Ebus Marli E ME   van Sluis Peter P   Hakkert Anne A   van Wezel Esther E   van der Schoot C Ellen CE   Westerhout Ellen M EM   Schulte Johannes H JH   Tytgat Godelieve A GA   Dolman M Emmy M ME   Janoueix-Lerosey Isabelle I   Gerhard Daniela S DS   Caron Huib N HN   Delattre Olivier O   Khan Javed J   Versteeg Rogier R   Schleiermacher Gudrun G   Molenaar Jan J JJ   Maris John M JM  

Nature genetics 20150629 8

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  ...[more]

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