EGAGenomicsRogier Versteeghttps://ega-archive.org/dacs/EGAC00001000321EGAEGA DAC EGAC00001000321EGAr.versteeg@amc.uva.nlThe 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.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 JMfalseAMC Dept. OncogenomicsData Access Committee EGAC00001000321EGAC00001000321960626121087EGAS00001001183EGAD00001001360