American Association for Cancer Research
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Supplementary Tables from RAS–MAPK Pathway-Driven Tumor Progression Is Associated with Loss of CIC and Other Genomic Aberrations in Neuroblastoma

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posted on 2023-03-31, 02:05 authored by Thomas F. Eleveld, Linda Schild, Jan Koster, Danny A. Zwijnenburg, Lindy K. Alles, Marli E. Ebus, Richard Volckmann, Godelieve A. Tijtgat, Peter van Sluis, Rogier Versteeg, Jan J. Molenaar

Supplementary Table 1: Public datasets used in this study, Supplementary Table 2: gRNA sequences against CIC, NF1 and DMD, Supplementary Table 3: Primers used for RT-qPCR experiments, Supplementary Table 4: Genes differentially expressed in the various model systems, Supplementary Table 5: Enrichment analysis of Hallmark gene sets , Supplementary Table 6: Statistical analysis of the role of RAS-MAPK activation in survival, Supplementary Table 7: Known RAS-MAPK activating mutations in our tumor series

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Kinder Kankervrij Foundation

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ARTICLE ABSTRACT

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.Significance: This work identifies CIC as a powerful tumor suppressor affecting the RAS-MAPK pathway in neuroblastoma and reinforces the importance of mutation-driven activation of this pathway in cancer. Cancer Res; 78(21); 6297–307. ©2018 AACR.

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