IDH Mutations in Chondrosarcoma: Case Closed or Not?

SIMPLE SUMMARY: Chondrosarcomas are cartilage tumours that often harbour a mutation in one of the isocitrate dehydrogenase (IDH) genes. IDH mutations are important drivers at the beginning of cartilage tumour development, but their role in later stages remains unclear. However, other IDH mutant tumour types do show an influence of this mutation on patient outcomes and therapies that specifically kill these IDH mutant tumour cells. Factors that could explain this discrepancy in the role of IDH mutations are differences in tumour type, elevated oncometabolite levels, the type of model used in preclinical studies (natural vs. introduced IDH mutation), and additional (epi)genetic alterations. The latter influence the downstream biological effects of an IDH mutation, and recent studies have indeed identified subgroups within IDH wildtype and mutant chondrosarcomas. Future studies should build upon these subgroups to improve the identification of effective treatments and biomarkers that predict which patients will benefit from these therapies. ABSTRACT: Chondrosarcomas are malignant cartilage-producing tumours that frequently harbour isocitrate dehydrogenase 1 and -2 (IDH) 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 of IDH mutations remains unclear and preclinical studies have not identified effective treatment modalities (in)directly targeting these mutations. In contrast, the IDH mutation status is a prognostic factor in other cancers, and IDH mutant inhibitors as well as therapeutic strategies targeting the underlying vulnerabilities induced by IDH mutations 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 the IDH mutation functions is an important factor to consider when investigating potential therapeutic strategies or patient outcomes. These findings imply that the dichotomy between IDH wildtype 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 within IDH wildtype and mutant chondrosarcoma.