What does this research mean for the field?

Integrating sarcoma-specific RNA-sequencing with comprehensive genomic profiling significantly increases the diagnostic yield of actionable fusions compared to CGP alone, and reveals that fusion-positive sarcomas frequently express PD-L1 despite low tumor mutational burden. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

The study aims to explore the molecular and immunological characteristics of fusion-driven sarcomas for improved clinical outcomes.

May 30, 2026

Clinical actionability and molecular landscapes of fusion-driven sarcomas: A multi-modal integration analysis of comprehensive genomic profiling, targeted RNA-sequencing, and PD-L1 expression.

Key Points

The study aims to explore the molecular and immunological characteristics of fusion-driven sarcomas for improved clinical outcomes.
Data from patients with sarcomas tested using pan-cancer Comprehensive Genomic Profiling (CGP) and targeted RNA-seq were analyzed (n=1,443).
PD-L1 expression was evaluated using CLIA graded immunohistochemistry (IHC).
The analysis included the prevalence of fusions and associations with TMB and other genetic alterations.
5.6% (29/517) of patients with CGP expressed a fusion; 28.1% (406/1,443) in targeted RNA-seq.
144 out of 295 unique detected fusions were determined to be pathogenic/likely pathogenic.
69% of fusion-positive sarcomas expressed PD-L1, while 84% of fusion-negative sarcomas were also positive for PD-L1.

Abstract

e23525 Background: Sarcomas are a heterogeneous group of mesenchymal malignancies frequently driven by pathognomonic chromosomal translocations. A complete molecular and immunological landscape of sarcoma patients requires DNA, RNA, and Immuno-Oncology biomarker testing. This study integrates fusion prevalence with other molecular and immunotherapy biomarker characterization in community-based sarcoma patients. Methods: Data was obtained from patients with a broad range of sarcomas tested in our clinical laboratory with a pan-cancer Comprehensive Genomic Profiling (CGP) assay, which tests DNA mutations and CNVs on 517 genes and fusions on 55 genes by RNA-seq (n=517) or with a targeted RNA-seq Sarcoma Fusion panel interrogating 97 genes (n=1,443). For SNV/CNV and TMB associations, only data from the CGP tested patients were analyzed. PD-L1 expression was determined by a CLIA grade IHC with disease-specific clones. An IRB-approved protocol was followed. Results: We found that 5.6% (29/517) of patients tested with the CGP assay expressed a fusion, whereas 28.1% (406/1443) tested positive in a sarcoma fusion-enriched RNA-seq clinical assay. Of the 295 unique fusions detected, 266 were observed in patients tested with the sarcoma panel, of which 189 were covered only by this panel. We found that 144 fusions were pathogenic/likely pathogenic, 79 had diagnostic value, 25 were prognostic, and 36 could guide therapy selection. The most frequent fusions were EWSR1::FLI1 (34), COL1A1::PDGFB (26), NAB2::STAT6 (25), CIC::DUX4 (23), JAZF1::SUZ12 (22), CEP170::RAD51B (21), FUS::DDIT3 (20), SS18::SSX1 (18), FUS::CREB3L2 (15), and EWSR1::NR4A3 (11). In the CGP fusion-positive subgroup, TP53 was the most frequently altered gene, followed by KIT, TERT, CHEK2, and KMT2A. Concurrent PDL1 IHC was ordered for 168/1960 of the patients. While 69% of fusion-positive patients expressed PD-L1, 84% of fusion-negative patients were PD-L1 positive. TMB was low in 83% (429/516) of the CGP tested sarcomas. However, while TMB was High (10.2-12.5 Mut/Mb) in 10% (3/29) of the fusion-positive patients, a wider TMB High range (10.2-482 Mut/Mb) was observed in 17% (84/487) of fusion-negative patients. Conclusions: CGP testing integrated with sarcoma-specific RNA-seq identifies actionable fusions in nearly one-third of community patients tested, offering a significantly higher diagnostic yield for fusions than CGP alone. Fusion-positive sarcomas exhibit a unique PD-L1 protein expression profile—frequently PD-L1 positive despite low TMB—suggesting a distinct immunobiological class that may bypass traditional TMB-based immunotherapy stratification. Utilizing multi-modal DNA/RNA and PD-L1 protein testing is critical for maximizing diagnostic, prognostic, and therapeutic precision in sarcoma clinical care.

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