(P 127) AN INTEGRATED CLINICAL GENOMIC AND TRANSCRIPTOMIC SUBGROUPING OF CENTRAL CHONDROSARCOMA

Objective: Central conventional chondrosarcoma, a malignant cartilage-producing bone tumor, is the second most-common bone sarcoma. Chondrosarcomas are histologically graded, which is so far the best predictor of survival. Early mutations in isocitrate dehydrogenase (IDH)-1 and -2 genes are frequent, leading to the production of the oncometabolite D-2-hydroxyglutarate, which affects DNA methylation, resulting in a preferred chondrogenic differentiation over osteogenic differentiation of mesenchymal stem cells, which are currently considered the precursor cells of chondrosarcoma. DNA methylation profiling has previously revealed distinct profiles between IDH mutant and wild-type chondrosarcomas, but the presence of further DNA methylation subgroups indicates that classification based solely on IDH status is too simplistic.

Methods: In this study, we aim to identify biological subgroups in a total of 116 chondrosarcomas by integrating clinical data, IDH mutation status, gene expression and genome wide loss of heterozygosity (gwLOH).

Results: Clinical associations were observed between several factors, including sex and histological grade, as well as tumor site and IDH mutation status. RNAseq and gwLOH confirmed the distinction between IDH wild-type and IDH mutant chondrosarcomas, where the number of chromosome arms affected by LOH was significantly higher in IDH wild-type tumors compared to IDH mutant tumors. However, no clear subgroups emerged within each IDH group. Further clustering on RNA expression of differentiation markers identified subgroups characterized by chondrogenic, osteogenic, resting chondrocyte, or dedifferentiated profiles. These different subgroups showed a specific clinical presentation and suggest different precursor cells.

Conclusion: Instead of a simple dichotomy between IDH mutant and IDH wild-type, our integrated approach highlight interconnected clinical, genomic, and transcriptomic patterns that offer a more nuanced view of chondrosarcoma biology and might potentially guide treatment stratification.