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

摘要

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 disease‐specific 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.