| Summary: | Background: Grade 2 and 3 and dedifferentiated chondrosarcomas (CS) are frequently associated with isocitrate dehydrogenase (<i>IDH</i>) mutations and often exhibit a poor clinical outcome. Treatment is limited mainly to surgery. Defining <i>IDH</i> status (wild type (WT) and mutant) and the associated transcriptome may prove useful in determining other therapeutic options in these neoplasms. Methods: Formalin-fixed paraffin-embedded material from 69 primary and recurrent grade 2, 3 and dedifferentiated CS was obtained. DNA sequencing for <i>IDH1</i> and <i>IDH2</i> mutations (<i>n</i> = 47) and RNA sequencing via Nextseq 2000 (<i>n</i> = 14) were performed. Differentially expressed genes (DEGs) were identified and used to predict aberrant biological pathways with Ingenuity Pathway Analysis (IPA) software (Qiagen). Gene Set Enrichment Analyses (GSEA) using subsets C3, C5 and C7 were performed. Differentially expressed genes were validated by immunohistochemistry. Outcome analysis was performed using the Wilcoxon test. Results: A set of 69 CS (28 females, 41 males), average age 65, distributed among femur, pelvis, humerus, and chest wall were identified from available clinical material. After further selection based on available <i>IDH</i> status, we evaluated 15 <i>IDH</i> WT and 32 <i>IDH</i> mutant tumors as part of this dataset. Out of 15 <i>IDH</i> WT tumors, 7 involved the chest wall/scapula, while 1 of 32 mutants arose in the scapula. There were far more genes overexpressed in <i>IDH</i> WT tumors compared to <i>IDH</i> mutant tumors. Furthermore, <i>IDH</i> WT and <i>IDH</i> mutant tumors were transcriptomically distinct in the IPA and GSEA, with <i>IDH</i> mutant tumors showing increased activity in methylation pathways and endochondral ossification, while <i>IDH</i> WT tumors showed more activity in normal matrix development pathways. Validation immunohistochemistry demonstrated expression of WT1 and AR in <i>IDH</i> WT tumors, but not in <i>IDH</i> mutants. SATB2 was expressed in <i>IDH</i> mutant tumors and not in WT tumors. Outcome analysis revealed differences in overall survival between mutant and WT tumors (<i>p</i> = 0.04), dedifferentiated mutant and higher-grade (2, 3) mutant tumors (<i>p</i> = 0.03), and dedifferentiated mutant and higher-grade (2, 3) WT tumors (<i>p</i> = 0.03). The longest survival times were observed in patients with higher-grade WT tumors, while patients with dedifferentiated mutant tumors showed the lowest survival. Generally, patients with <i>IDH</i> WT tumors displayed longer survival in both the higher-grade and dedifferentiated groups. Conclusions: Grade 2, 3 and dedifferentiated chondrosarcomas are further characterized by <i>IDH</i> status, which in turn informs transcriptomic phenotype and overall survival. The transcriptome is distinct depending on <i>IDH</i> status, and implies different treatment targets.
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