FGFR3-TACC3 fusion: multi-omics and machine learning characterization across tumor types

Background: The FGFR3-TACC3 (FGFR3-TACC3) fusion is a recurrent oncogenic alteration observed in gliomas, urothelial, and head and neck cancers. This fusion drives constitutive FGFR3 kinase activation and disrupts mitotic spindle organization through TACC3, leading to uncontrolled proliferation and transcriptional reprogramming. To elucidate the molecular landscape and therapeutic vulnerabilities of FGFR3-TACC3-positive tumors, we integrated genomic, transcriptomic, and computational analyses. Methods: Transcriptomic data from TCGA cohorts were analyzed to compare FGFR3-TACC3-positive and wild-type tumors. Differentially expressed genes (fold change > 2 or < -2) were intersected with druggability databases to identify actionable targets. In parallel, we analyzed 58 FGFR3-TACC3 fusion samples and 9,642 non-fusion cases to determine recurrently mutated genes and enriched Gene Ontology (GO) terms. A combined neural network and random forest classifier was trained on mutational and functional features to discriminate fusion from non-fusion profiles. Results: FGFR3-TACC3 fusion tumors exhibited a distinct transcriptional and mutational signature, including 1,984 upregulated and 2,504 downregulated genes, with enrichment in RTK/MAPK signaling, mitotic spindle assembly, and vesicle transport pathways. Integration with pharmacologic databases revealed 48 co-expressed druggable genes, encompassing oncogenic kinases (FGFR3, EGFR, CDK4, PDGFRA, NTRK3) and neurotransmission-associated receptors (OXTR, ADORA1, GRIA3/4). Machine-learning analysis identified 9 recurrently mutated genes and 69 informative GO terms, achieving an AUC of 0.85 and accuracy of 0.79, highlighting a robust functional signature of FGFR3-TACC3 fusion tumors. Conclusions: This integrated multi-omics and machine-learning study suggests a functional, transcriptional, and pharmacologic landscape of FGFR3-TACC3 fusion-driven cancers. The combined mutation-GO-transcriptome framework uncovers potential druggable co-dependencies and provides hypotheses for rational combination strategies and precision therapies for FGFR3-TACC3-positive tumors that warrant experimental validation.