Genomic characterization of conventional, dedifferentiated, and mesenchymal chondrosarcoma: A 550-patient multicenter analysis.

11528 Background: The rarity of chondrosarcoma has historically impeded efforts and systematic genomic characterization. However, large, standardized, multi-center databases, such as the AACR Project GENIE, along with other, independent studies, have enabled genetic profiling of hundreds of patients with these cancers. Methods: The following datasets were accessed through cBioPortal: the GENIE Cohort v18.0; msk_impact_2017; metastatic_solid_tumors_mich_2017; pog570_bcgsc_2020; msk_ch_2020; msk_ch_ped_2021; sarcoma_msk_2022; sarcoma_mskcc_2022; mixed_kunga_msk_2022; msk_ctdna_vte_2024; and sarcoma_ucla_2024. These datasets included 550 unique patients: 453 conventional chondrosarcoma (CHS), 42 dedifferentiated chondrosarcoma (DDCHS), and 55 mesenchymal chondrosarcoma (MCHS). Mutational and structural variant data were also extracted from each data set and ranked by frequency. This ranked list of genes was then analyzed using g:Profiler enrichment analysis software. Dunn’s test with Benjamini-Hochberg correction following Kruskal-Wallis test was performed for statistical analysis. Results: The average age at biopsy was 52 for CHS, 63 for DDCHS, and 32 for MCHS. DDCHS displayed the greatest genomic instability, with significantly elevated mutation count and tumor mutation burden (TMB) compared to CHS and MCHS ( p < 0.001). Despite the higher TMB in DDCHS, the most frequently mutated genes were highly conserved between CHS and DDCHS, with six of the 20 most frequently mutated genes being shared between them. In contrast, MCHS shared only two of the 20 most frequently mutated genes with CHS and DDCHS. TP53 , IDH1 and -2 , and TERT were frequently mutated in both CHS and DDCHS. Enrichment analysis indicated that DNA repair pathways were among the most frequently altered in both diseases. These pathways, while still perturbed in MCHS, appeared less prominently, with genes involved in chromatin organization being frequently mutated. Moreover, Enrichment analysis of structurally variant genes in CHS also showed frequent alterations in chromatin organizing genes, along with genes involved in NOTCH signaling. While structural variant genes were not reported with enough frequency in DDCHS and MCHS to permit the analysis, the HEY1-NCOA2 fusion product was frequently detected in MCHS. Conclusions: The results of this multi-institutional bioinformatics survey confirms established observations that IDH1 and -2 mutations are the most common genetic alterations in CHS following TP53 . DDCHS bears a similar but more advanced mutational signature with greater genomic instability. MCHS harbors a distinct mutational profile defined by the characteristic HEY1-NCOA2 fusion. Despite these differences, all three subtypes share enrichment in mutations affecting genomic integrity pathways, suggesting this as a common feature of chondrosarcoma biology.