IDH Mutations in Chondrosarcoma: Case Closed or Not?

IDH IDH IDH IDH IDH IDH IDH Chondrosarcomas are malignant cartilage-producing tumours that frequently harbour isocitrate dehydrogenase 1 and -2 () gene mutations. Several studies have confirmed that these mutations are key players in the early stages of cartilage tumour development, but their role in later stages remains ambiguous. The prognostic value ofmutations remains unclear and preclinical studies have not identified effective treatment modalities (in)directly targeting these mutations. In contrast, themutation status is a prognostic factor in other cancers, and IDH mutant inhibitors as well as therapeutic strategies targeting the underlying vulnerabilities induced bymutations seem effective in these tumour types. This discrepancy in findings might be ascribed to a difference in tumour type, elevated D-2-hydroxyglutarate levels, and the type of in vitro model (endogenous vs. genetically modified) used in preclinical studies. Moreover, recent studies suggest that the (epi)genetic landscape in which themutation functions is an important factor to consider when investigating potential therapeutic strategies or patient outcomes. These findings imply that the dichotomy betweenwildtype and mutant is too simplistic and additional subgroups indeed exist within chondrosarcoma. Future studies should focus on the identification, characterisation, and tailoring of treatments towards these biological subgroups withinwildtype and mutant chondrosarcoma.