Mutational profiling of chondrosarcoma across multicenter cohorts

Background: Molecular therapies for chondrosarcomas remain limited, in part due to the rarity of these cancers, which hampers efforts at broad genomic characterization. The establishment of large, standardized, multicenter databases, such as the AACR Project GENIE, along with subsequent individual studies, has begun to assemble an extensive mutational profile of this disease. This abstract provides a preliminary analysis of the mutational data from these studies. Methods: The GENIE Cohort v18.0, MSK Nature Communications Sarcoma 2022, and UCLA Cell 2024 sarcoma datasets, accessed via cBioPortal, were collated and analyzed. These datasets included patient information for conventional chondrosarcoma (CS), dedifferentiated chondrosarcoma (DDCS), and mesenchymal chondrosarcoma (MCS). Available data included patient age, sex, race, mutational profiles, and, for CS and DDCS, survival outcomes. Results: In total, the datasets encompassed 518 patients with chondrosarcoma: 428 CS, 38 DDCS, and 52 MCS. The average age at biopsy was 52 for CS patients, 63 for DDCS patients, and 33 for MCS patients. Women comprised 40.4%, 54.1%, and 55.8% of CS, DDCS, and MCS patients, respectively. Among patients with recorded race, the racial distribution was 74% White, 5% Black, 10% Asian, and 12% Other for CS; 89% White, 5% Black, 3% Asian, and 3% Other for DDCS; and 83% White, 13% Black, and 4% Other for MCS. The average mutation count per patient sample was 10.1 for CS, 5.4 for DDCS, and 2.6 for MCS. The top five most frequently mutated genes for each disease were as follows - CS: TP53 (124/439), IDH1 (113/437), IDH2 (35/423), KMT2D (15/186), and TERT (14/179); DDCS: TP53 (24/40), IDH1 (18/40), TERT (13/38), IDH2 (12/40), FLT4 (8/40); MCS: MAP3K13 (5/18), INSR (4/17), SDHA (5/23), KMT2D (4/24), and KMT5A (2/13). Median overall survival was 58 months for CS patients versus 25 months for DDCS patients. Notably, many of the most frequently mutated genes beyond TP53 , IDH1 , and IDH2 are involved in chromatin regulation and genomic stability ( KMT2A , KMT2D , TERT , etc.), and these mutations are more common in DDCS. Conclusion: This multicenter mutational analysis confirms that, after TP53 , the most frequently mutated genes in CS and DDCS are IDH1 and IDH2 . Mutations in genes involved in chromatin regulation and genomic stability are more prevalent in DDCS, which may contribute to its increased aggressiveness. These findings support ongoing efforts to target these pathways in chondrosarcoma.