Characterisation of isocitrate dehydrogenase 1/isocitrate dehydrogenase 2 gene mutation and the d‐2‐hydroxyglutarate oncometabolite level in dedifferentiated chondrosarcoma

Abstract

Aims: Dedifferentiated chondrosarcoma (DDCHS) is an aggressive type of chondrosarcoma that results from high-grade transformation of a low-grade chondrosarcoma. Mutations in the isocitrate dehydrogenase (IDH) 1 gene and the IDH2 gene that lead to increased D-2-hydroxyglutarate (2HG) oncometabolite production, promoting tumorigenesis, have been recently described in low-grade cartilaginous neoplasms. The aims of this study were to examine the prevalence of IDH mutations in a single-institution cohort of DDCHS cases and correlate 2HG levels with mutation status. Methods and results: We examined a series of 21 primary DDCHS cases by using Sanger sequencing and quantitative polymerase chain reaction genotyping to look for IDH1/IDH2 mutations, and evaluated the 2HG levels in formalin-fixed paraffin-embedded tumour and matched normal tissue samples by using a fluorometric assay. Seventy-six per cent of DDCHS cases (16/21) harboured a heterozygous IDH1 or IDH2 mutation. Six of 14 IDH-mutated DDCHS cases showed elevated 2HG levels in tumour tissue relative to matched normal tissue. There were no consistent histological or diseasespecific survival differences between IDH-mutated tumours and wild-type tumours. Conclusions: Our study confirms the frequent presence of a variety of IDH1 and IDH2 mutation variants, indicating that a sequencing-based approach is required for DDCHS if IDH is to be used as a diagnostic marker. Similarly to other IDH-mutated tumour types, IDH-mutated DDCHS cases show elevated 2HG levels, indicating that the oncometabolite activity of 2HG may contribute to DDCHS oncogenesis and progression.

Prognostic importance of IDH mutations in chondrosarcoma: An individual patient data meta‐analysis

“…The impact of IDH1 / 2 mutations on chondrosarcoma patient survival is unclear 12,16,17 . Lugowska et al indicated an association of IDH mutation with a shorter OS while other studies failed to establish this relationship 12,26 . This study concluded a negative impact of IDH mutation on patient OS, emphasizing the independent role of IDH mutation as a prognostic marker in chondrosarcomas.…”

“…Given the rarity of chondrosarcomas, 8 it was difficult to reach statistical significance when examining the prognosis of this tumor. Most of the published data failed to demonstrate the prognostic impact of IDH mutations in chondrosarcomas 17,23,26 . We incorporated nearly 500 cases of chondrosarcoma and highlighted that IDH mutation is an independent prognostic marker regardless of age, gender, tumor grades, and locations.…”

Biological Roles and Therapeutic Applications of IDH2 Mutations in Human Cancer

“…Dedifferentiated chondrosarcoma (DDCHS) is a kind of highgrade chondrosarcoma, which is transformed from low grade and has strong invasiveness (63). The frequency of IDH2 mutations in dedifferentiated chondrosarcoma is much higher than that of other chondrosarcomas (64). Researchers have found that up to 76% of IDH heterozygous mutations in DDCH, 39.1% of which are IDH2 mutations, 2-HG levels in tumor tissues are significantly higher than normal tissues (64).…”

“…The frequency of IDH2 mutations in dedifferentiated chondrosarcoma is much higher than that of other chondrosarcomas (64). Researchers have found that up to 76% of IDH heterozygous mutations in DDCH, 39.1% of which are IDH2 mutations, 2-HG levels in tumor tissues are significantly higher than normal tissues (64). Given the high incidence of IDH2 mutations in DDCHS, IDH2 can be used as a diagnostic marker for DDCHS.…”

Is the IDH Mutation a Good Target for Chondrosarcoma Treatment?

“…No mutations were found in peripheral chondrosarcoma or in the osteochondroma tissues tested, and both low-grade and high-grade chondrosarcomas exhibited the mutation. One Clear cell chondrosarcoma and mesenchymal chondrosarcoma do not harbour IDH1 or IDH2 mutations, as opposed to dedifferentiated chondrosarcoma which harbours a mutation in one of these genes in 50-76% of cases [34,50,51].…”