Abstract 7173: Comprehensive genomic profiling reveals novel insights into the genomic landscape of extraskeletal myxoid chondrosarcomas
Authors: Carl Philipp Schmitthenner, Franziska Evelt, Lucas Sebastian Scholl, Jessica Janke, Anna Kuntze, Santina Kirmse, Kim Falkenberg, Ilka Isfort, Ruth Berthold, Kornelius Kerl, Inga Grünewald, Eva Wardelmann, Wolfgang Hartmann, Marcel Trautmann
Journal: Cancer Research (2025)

Abstract Background: Extraskeletal myxoid chondrosarcomas (EMCs) are rare mesenchymal neoplasms comprising less than 3% of all soft tissue tumors. EMCs arise mainly from the deep soft tissues of the extremities, accompanied by high rates of recurrence and metastases. The molecular hallmarks of EMCs are cytogenetic NR4A3 rearrangements, generating chimeric NR4A3 fusion oncoproteins. The most common reciprocal translocation t(9;22)(q22;q12) results in a fusion of the EWS RNA-binding protein 1 gene (EWSR1) to the nuclear receptor subfamily 4 group A member 3 gene (NR4A3 or TEC; approximately 75% of cases). Although the oncogenic NR4A3 fusion transcripts appear to play a crucial role in EMC tumorigenesis and progression, the specific biological function and the mechanism of action remains to be defined. Comprehensive genomic profiling (CGP) and reliable molecular characterization of solid tumors using Next-Generation-Sequencing (NGS) technology has become a key tool to facilitate biomarker-matched therapy selection. With a broad spectrum of therapies already approved or currently tested in clinical trials, rapid and scalable detection of an evolving number of therapeutically relevant genomic alterations and complex biomarkers is required. Methods: This study combined NGS-based CGP and fusion gene analysis of 69 paraffin-embedded EMC tissue samples to systematically map the genomic landscape of EMC. We used the all-in-one OncoDEEP® in-house kit, integrating both (i) an DNA NGS panel larger than 1MB powered by Twist Bioscience hybrid capture technology in combination with (ii) OncoDNA’s bioinformatic data analysis and clinical interpretation software suite (OncoKDM) resulting in an integrated theranostic report. The CE-IVD approved assay covers single-nucleotide variants (SNVs), copy number variants (CNVs), deletions and insertions (indels) and loss of heterozygosity (LOH) in 638 genes and facilitates the assessment of key complex biomarkers / signatures such as homologous recombination deficiency (HRD), tumor mutational burden (TMB), or microsatellite instability (MSI). Results: Overall, more than 13, 600 variants have been identified, categorized as: pathogenic (0.1%), likely pathogenic (1.9%), variant of unknown significance (VUS; 13.3%), likely benign (6.3%) and benign (78.3%). TMB, HRD and MSI status were successfully assessed in more than 88% of all EMC samples. Furthermore, a novel NR4A3 fusion rearrangement was identified with the majority of EMC samples expressing the chimeric t(9;22) EWSR1::NR4A3 fusion transcript. Conclusions: This study provides a comprehensive genomic profile of EMC and uncovers novel genetic alterations, enhancing our understanding of its underlying pathogenesis. Gained genomic insights are anticipated to inform and refine future diagnostic criteria, potentially leading to more precise targeted therapies. Citation Format: Carl Philipp Schmitthenner, Franziska Evelt, Lucas Sebastian Scholl, Jessica Janke, Anna Kuntze, Santina Kirmse, Kim Falkenberg, Ilka Isfort, Ruth Berthold, Kornelius Kerl, Inga Grünewald, Eva Wardelmann, Wolfgang Hartmann, Marcel Trautmann. Comprehensive genomic profiling reveals novel insights into the genomic landscape of extraskeletal myxoid chondrosarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7173.