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Functional genomic analysis of adult and pediatric brain tumor isolates

ABSTRACT: Despite in-depth knowledge of the molecular features and oncogenic drivers associated with adult and pediatric brain tumors, identifying effective targeted therapies for these cancers remains challenging. To identify novel gene dependencies in adult and pediatric brain tumor isolates, we integrated data from functional genomic lethality screens in primary brain tumor isolates with machine learning network models from lethality screens performed in >900 cancer cell lines. Integrated network models revealed molecular and phenotypic features that predict candidate genetic dependencies in multiple brain tumor types, including: atypical teratoid rhabdoid tumors, diffuse intrinsic pontine gliomas, ependymomas, medulloblastomas, and glioblastomas (primary and recurrent). Some examples of dependencies and predictors include: ADAR and MX1 protein expression; EFR3A and low EFR3B expression; FBXO42 and spindle assembly checkpoint activation; FGFR1 and high FGF2 expression; and SMARCC2 in SMARCB1 mutated ATRT tumors. In general, the results demonstrate that large functional genetic data sets can be leveraged to identify, validate, and categorize gene dependencies and their associated biomarkers in primary tumor isolates. The results also highlight some of the challenges and limitations of this approach.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213269 | GEO | 2023/02/07

REPOSITORIES: GEO

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Project description:Pediatric brain cancer is the leading cause of disease-related mortality in children, and many aggressive tumors still lack effective treatment strategies. Despite extensive studies characterizing these tumor genomes, alternative transcriptional splicing patterns remain underexplored. Here, we systematically characterized aberrant alternative splicing across pediatric brain tumors, identifying pediatric high-grade gliomas (HGGs) among the most heterogeneous. Through integration with UniProt Knowledgebase annotations, we identified 12,145 splice events in 5,424 genes, leading to functional changes in protein activation, folding, and localization. We discovered that the master splicing factor and cell-cycle modulator, CDC-like kinase 1 (CLK1), is aberrantly spliced in HGGs to include exon 4, resulting in a gain of two phosphorylation sites and subsequent activation of CLK1. Inhibition of CLK1 with Cirtuvivint in the pediatric HGG KNS-42 cell line significantly decreased both cell viability and proliferation in a dose-dependent manner. Morpholino-mediated depletion of CLK1 exon 4 splicing reduced RNA expression, protein abundance, and cell viability. Notably, KNS-42 cells treated with the CLK1 exon 4 morpholino demonstrated differential expression impacting 173 cancer genes and differential splicing with loss or gain of a functional site in 529 cancer genes. These genes were enriched for cancer-associated pathways, with 20 identified as significant gene dependencies in pediatric HGGs. Our findings highlight a dependency of pediatric HGGs on CLK1 and its roles contributing to tumor splicing heterogeneity through transcriptional dysregulation of splicing factors and direct transcriptional modulation of oncogenes. Overall, aberrant splicing in HGGs and other pediatric brain tumors represents a potentially targetable oncogenic pathway contributing to tumor growth and maintenance. Continued investigation of these mechanisms is essential for developing new effective treatment strategies for these patients.

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Functional genomic analysis of adult and pediatric brain tumor isolates

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