Abstract B012: Clinical Outcomes and Characterization of the Tumor Microenvironment in Fusion-Positive Cutaneous Melanoma

Abstract Background: Oncogenic gene fusions in cutaneous melanoma are uncommon and their clinical relevance in terms of prognosis and treatment has been poorly delineated. Outcomes to therapy, and characterization of the immune landscape associated with these fusion events have not been previously explored. Methods: Comprehensive genomic profiling (DNA + RNA sequencing) was performed on 13,835 melanoma cases submitted to Caris Life Sciences (Phoenix, AZ) between 2015 and 2025. Pathogenic and likely pathogenic fusions were identified using an RNA-based fusion detection pipeline and integrated with mutational, clinical, and therapeutic outcome data. Immune cell infiltration in the tumor microenvironment was estimated by deconvolution of the RNAseq data using Quantiseq. Real-world overall survival (OS[AE1] ) was obtained from insurance claims data, calculated from start of biopsy or immune checkpoint inhibitors (ICI) to last contact. Mann-Whitney U and X2/Fisher-Exact tests were applied, with p-values adjusted (p < 0.05). Results: A total of 388 melanoma cases (2.8%) harbored pathogenic or likely pathogenic fusions. Across melanoma subtypes, BRAF fusions were most prevalent (39%), followed by RAF1 (14%) and ALK (9%) fusions. Overall fusion prevalence was significantly higher in BRAF/NRAS/NF1 wild-type (WT) compared with mutant cohorts (9.7% vs 0.7%; p