Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations
Eleveld, T.F., Oldridge, D.A., Bernard, V., Koster, J., Daage, L.C., Diskin, S.J., Schild, L., Bentahar, N.B., Bellini, A., Chicard, M., Lapouble, E., Combaret, V., Legoix-Né, P., Michon, J., Pugh, T.J., Hart, L.S., Rader, J., Attiyeh, E.F., Wei, J.S., Zhang, S., Naranjo, A., Gastier-Foster, J.M., Hogarty, M.D., Asgharzadeh, S., Smith, M.A., Guidry Auvil, J.M., Watkins, T.B.K., Zwijnenburg, D.A., Ebus, M.E., van Sluis, P., Hakkert, A., van Wezel, E., van der Schoot, C.E., Westerhout, E.M., Schulte, J.H., Tytgat, G.A., Dolman, M.E.M., Janoueix-Lerosey, I., Gerhard, D.S., Caron, H.N., Delattre, O., Khan, J., Versteeg, R., Schleiermacher, G., Molenaar, J.J., Maris, J.M., 2015.
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.