Genomic Characterization of Chondrosarcoma Reveals Potential Therapeutic Targets.

Abstract

Chondrosarcomas are rare cancers of cartilage with limited systemic therapy options. To identify potential therapeutic targets, this study investigated the molecular and immune landscape of three chondrosarcoma subtypes using a large database of clinical-grade sequencing results. Deidentified records from patients with a histologic diagnosis of conventional, dedifferentiated, or mesenchymal chondrosarcoma sequenced by the Tempus xT DNA assay were included. Microsatellite instability (MSI) and tumor mutational burden (TMB) were determined from sequencing data. The expression of PD-L1 and mismatch repair enzymes was evaluated in cases with available immunohistochemistry (IHC) data. Of the 149 patients, 103 had conventional chondrosarcoma, 31 dedifferentiated chondrosarcoma, and 15 mesenchymal chondrosarcoma. Across the cohort, 44% (n = 65) had an <i>IDH1</i> or <i>IDH2</i> mutation. No cases were MSI high. One conventional chondrosarcoma patient had a TMB >10 mut/Mb. Among 112 patients with available PD-L1 IHC, 10% of conventional (n = 7), 45% of dedifferentiated (n = 13), and 17% of mesenchymal cases (n = 2) were PD-L1-positive. The most common somatic alterations were in <i>IDH1</i> (34%) and <i>TP53</i> (28%) in conventional chondrosarcoma; <i>TP53</i> (68%), <i>TERT</i> (65%), <i>IDH1</i> (39%), <i>IDH2</i> (39%), <i>CDKN2A</i> (35%), and <i>CDKN2B</i> (35%) in dedifferentiated chondrosarcoma; and <i>HEY1-NCOA2</i> fusions (87%) and <i>CDKN2A</i> (20%) in mesenchymal chondrosarcoma. <i>MTAP</i> was deleted in >10% of each subtype, and potentially actionable <i>PDGFRB</i> mutations were identified in 13% of dedifferentiated chondrosarcomas. These findings reinforce therapeutic efforts to target IDH signaling in chondrosarcoma, provide insight into varied subpopulation response to immune checkpoint inhibitors, and identify new potential therapeutic targets for clinical development in chondrosarcoma.