Presence of IDH2 and TP53 mutations significantly reduces survival of patients with chondrosarcoma.

Abstract

Chondrosarcoma (CS) has a prognosis largely influenced by tumor grade. Although IDH mutations have been reported in CS, impact on patient`s survival remains controversial. This study aims to assess prognostic relevance of IDH mutations on disease-specific survival (DSS), metastasis-free survival (MFS), and local recurrence-free survival (RFS), in a large cohort of CS patients. The authors retrospectively analyzed CS samples from patients treated at two German musculoskeletal tumor centers. Tumor-specific mutations, including IDH, TP53, TERT promoter, and CDKN2A/B, were identified through DNA isolation and next-sequencing. Molecular findings were correlated with oncologic outcomes to evaluate their prognostic significance. A total of 109 patients (53 females, 56 males; median age, 57 (16-89) years) were included. Tumor grades were G1/ACT (39%), G2 (41%), and G3/dedifferentiated (10%). Median follow-up was 3.8 years with mortality of 17%. IDH mutations were detected in 59% (IDH1: 64%, IDH2: 36%), with dedifferentiated CS showing highest IDH mutation rate (91%), particularly IDH2. IDH2-mutations were associated with significantly worse DSS compared to IDH-wild-type or IDH1-mutated tumors, independent of tumor grade. Specifically, IDH1-R132C mutation correlated with significantly improved DSS compared to R132G, and IDH2-R172S variant showed longest DSS and MFS, whereas IDH2-R172T was linked to significant poor outcomes. In multivariable analysis, IDH2 and TP53 mutations were independent predictors of worse survival. IDH2 and TP53 mutations are enriched in dedifferentiated CS and are significant, independent predictors of adverse survival, regardless of tumor grade. These findings support IDH2 mutation status as clinically meaningful prognostic biomarker that may allow risk stratification and clinical decision-making in CS patients.