RAS-MAPK pathway-driven tumor progression is associated with loss of CIC and other genomic aberrations in neuroblastoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-11, Vol.78 (21), p.6297-6307
• Main Authors: Eleveld, Thomas F, Schild, Linda, Koster, Jan, Zwijnenburg, Danny A, Alles, Lindy K, Ebus, Marli E, Volckmann, Richard, Tytgat, Godelieve A M, van Sluis, Peter, Versteeg, Rogier, Molenaar, Jan J
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-18-1045

Mutations affecting the RAS-MAPK pathway frequently occur in relapsed neuroblastoma tumors, which suggests that activation of this pathway is associated with a more aggressive phenotype. To explore this hypothesis, we generated several model systems to define a neuroblastoma RAS-MAPK pathway signature. Activation of this pathway in primary tumors indeed correlated with poor survival and was associated with known activating mutations in ALK and other RAS-MAPK pathway genes. Integrative analysis showed that mutations in PHOX2B, CIC, and DMD were also associated with an activated RAS-MAPK pathway. Mutation of PHOX2B and deletion of CIC in neuroblastoma cell lines induced activation of the RAS-MAPK pathway. This activation was independent of phosphorylated ERK in CIC knockout systems. Furthermore, deletion of CIC caused a significant increase in tumor growth in vivo. These results show that the RAS-MAPK pathway is involved in tumor progression and establish CIC as a powerful tumor suppressor that functions downstream of this pathway in neuroblastoma.