(P 44) A SYSTEMATIC REVIEW OF FUSION-DRIVEN SARCOMAS

Objective: Sarcomas are rare and complex malignancies, approximately 30% of which are defined by characteristic gene fusions that serve as diagnostic, prognostic, and therapeutic biomarkers. These fusions provide a powerful tool across various types of sarcomas, facilitating diagnosis and treatment precision approaches. In this review, we summarize current knowledge on major fusion-driven sarcoma categories and outline a proposed systematic review aimed at evaluating emerging diagnostic methodologies and targeted therapies.We also highlight how fusion genes are influencing the future of sarcoma care.

Methods: We conducted a comprehensive review of published literature from 2015–2025 across PubMed, Web of Science, Cochrane, and ClinicalTrials.gov. We focused on research involving human fusion-positive sarcomas, molecular diagnostics, and targeted therapies. A systematic review protocol following PRISMA guidelines has been developed and screening is currently in progress.

Results: We found that sarcoma-related fusion genes fall into four major categories: 1. Transcription Factor Fusions such as EWSR1-FLI1, SS18-SSX, PAX3-FOXO1 which define tumor lineage but remain difficult to target directly. 2. Tyrosine Kinase Fusions including NTRK, ALK, and COL1A1-PDGFB are highly actionable with FDA-approved therapies like larotrectinib, imatinib, and others. 3. Chromatin Remodeling Fusions like BCOR- and NAB2- rearrangements highlight the potential for epigenetic targeting such as EZH2 inhibitors. 4. Rare and Novel Fusions including CIC-DUX4 and YAP1-TFE3, are increasingly identified through advances in RNA-based sequencing. RNA-based next generation sequencing (NGS) is revolutionizing fusion detection and improving diagnostic precision. Hi-C sequencing is an emerging DNA-based NGS that may detect cryptic fusions and potential therapeutic targets. Targeted therapies, including kinase inhibitors, epigenetic modulators, and emerging immunotherapies are under investigation preclinically and within clinical trials.

Conclusion: With the continued discovery of tumor-specific oncogenes, understanding fusion protein activity is essential for developing efficacious systemic therapies. Barriers in this path include the rarity of fusions, limited actionability, and lack of comprehensive fusion registries. Our proposed systematic review aims to assess the evolving clinical utility of fusion-targeted diagnostics and therapies. Multi-institutional/national collaborations are essential to advance fusion-targeted care of these rare tumors, particularly with discovery of novel genes using more sensitive technologies. Harnessing the clinically relevant fusion gene biology holds promise for improving outcomes in patients with these rare and often aggressive tumors.