Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations.

A 40x image of a typical neuroblastoma with rosette formation. Image credit: Dr. Maria Tsokos, National Cancer Institute

A 40x image of a typical neuroblastoma with rosette formation. Image credit: Dr. Maria Tsokos, National Cancer Institute

Eleveld TF, Oldridge DA, Bernard V, Koster J, Colmet Daage L, Diskin SJ, Schild L, Bentahar NB, Bellini A, Chicard M, Lapouble E, Combaret V, Legoix-Né P, Michon J, Pugh TJ, Hart LS, Rader J, Attiyeh EF, Wei JS, Zhang S, Naranjo A, Gastier-Foster JM, Hogarty MD, Asgharzadeh S, Smith MA, Guidry Auvil JM, Watkins TB, Zwijnenburg DA, Ebus ME, van Sluis P, Hakkert A, van Wezel E, van der Schoot CE, Westerhout EM, Schulte JH, Tytgat GA, Dolman ME, Janoueix-Lerosey I, Gerhard DS, Caron HN, Delattre O, Khan J, Versteeg R, Schleiermacher G, Molenaar JJ, Maris JM.

Nature Genetics

August 01, 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.

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Last updated: August 20, 2018