Abstract 1770: Right oncogene, wrong tumor - CBL mutations in pediatric CNS and solid tumors

Abstract The molecular analysis of individual patient tumors by personalized medicine programs like the Zero Childhood Cancer Program (ZERO) enables the detection of potentially targetable lesions, unlocking new therapeutic opportunities for patients. Somatic mutations in the E3-ubiquitin ligase, CBL, are known to activate receptor tyrosine kinases (RTKs) in cancer and have been exclusively characterized in hematological malignancies. This includes acute myeloid leukemia, where CBL mutations lead to FLT3 activation. Using molecular data from ZERO we have identified known and novel CBL variants in novel tumor contexts. Our findings raise the possibility that CBL mutation may be a marker of RTK activation in a range of paediatric cancer types and may represent a group of patients who could benefit from tyrosine kinase inhibitor (TKI) therapy. We analyzed whole genome and RNA sequencing data from the ZERO cohort and identified 26 somatic CBL variants in 22 individual patients, the majority of which were in CNS tumors (14 patients). In 8 patients with CNS tumors, we identified missense and splicing variants, which were either novel or not previously seen in this tumor type, that are predicted to have a functional impact on CBL E3 ligase activity due to their location in the linker region or RING finger domain of CBL. Interestingly, most of these patients did not fall into a pre-defined DNA methylation-based subtype classification of CNS tumors and had no significant upregulation of RTK genes. In addition to the novel variants, we identified an established oncogenic CBL deletion variant, CBL exon 8/9 deletion (CBL ex8/9Δ), in novel tumor types - neuroblastoma and a germ cell tumor. Functionally, we show that overexpression of CBL ex8/9Δ enhances cell proliferation and maintains EGFR signaling by blocking CBL mediated degradation of phosphorylated EGFR in neuroblastoma cells. In this study, we demonstrate that CBL is mutated in a range of pediatric cancer types beyond hematological malignancies and may represent a marker of RTK activation and a new target for high-risk patients with limited therapeutic options. Citation Format: Lauren M. Brown, Chelsea Mayoh, Pablo Acera Mateos, Antoine De Weck, Robert Salomon, Teresa Sadras, Neevika Manoharan, Marie Wong, Mark J. Cowley, Paul G. Ekert. Right oncogene, wrong tumor - CBL mutations in pediatric CNS and solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1770.