Prognostic Role of TERT Mutations in Chondrosarcoma: Associations with Dedifferentiation, Survival, and IDH/TERT Co-Mutations

Background/Objectives: Chondrosarcoma is a clinically heterogeneous malignancy, and the prognostic role of its genetic features remains incompletely defined. While isocitrate dehydrogenase (IDH) mutations are well characterized, the significance of less common alterations—particularly telomerase reverse transcriptase (TERT) promoter mutations—remains unclear. This study aimed to define the genomic profile of chondrosarcoma and evaluate the prognostic relevance of TERT mutations, alone and in combination with IDH mutations. Methods: We retrospectively analyzed 91 patients with chondrosarcoma, including 54 patients with available next-generation sequencing data for genomic analyses. Tumors were assessed for mutations in IDH, TERT, TP53, and groups of genes involved in key cellular functions (e.g., cell cycle control, chromatin regulation). Associations with tumor characteristics were evaluated, recurrence outcomes were assessed using logistic regression, and overall survival was analyzed using Kaplan–Meier and Cox models adjusted for tumor subtype, grade, and size. Results: IDH mutations were present in 52% of tumors; other alterations included TP53 (16%), TERT (7.7%), chromatin-related genes (14%), and cell cycle genes (8.8%). TERT mutations were enriched in dedifferentiated tumors (p = 0.017) and occurred exclusively in grade 3 disease (“p < 0.001”). TERT-mutant tumors were associated with worse overall survival upon unadjusted analysis (HR 7.02, p = 0.024), but not after adjustment (HR 3.81, p = 0.160). All TERT mutations co-occurred with IDH mutations, and this subgroup had particularly poor survival (HR 7.76, p = 0.022), albeit limited by small numbers. Conclusions: These findings suggest that specific mutations, alone or in combination, may influence clinical outcomes by reflecting more aggressive tumor biology. TERT mutations, particularly with concurrent IDH mutations, may identify high-risk patients and complement established prognostic factors. Further validation is needed.