Characterization of IDH1/IDH2 Mutation and D-2-Hydroxyglutarate Oncometabolite Level in Dedifferentiated Chondrosarcoma.Histopathology 2019H
Dedifferentiated chondrosarcoma (DDCHS) is an aggressive type of chondrosarcoma that results from high-grade transformation of a low-grade chondrosarcoma. Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations have been recently described in low-grade cartilaginous neoplasms which lead to increased D-2-hydroxyglutarate (2HG) oncometabolite production, promoting tumorigenesis.
To examine the prevalence of IDH mutations in a single institution cohort of DDCHS and correlate 2HG levels to mutation status.
METHODS AND RESULTS
We examined a series of 21 primary DDCHS using Sanger sequencing and qPCR genotyping to interrogate for IDH1/2 mutations, and evaluated the level of 2HG in formalin-fixed paraffin-embedded (FFPE) tumor and matched normal tissue samples using a fluorometric assay. 76% of DDCHS (16/21) harbored a heterozygous IDH1 or IDH2 mutation. 6/14 IDH-mutated DDCHS showed elevated 2HG in tumor relative to matched normal tissue. There were no consistent histologic or disease specific survival differences between IDH-mutated tumors and wild-type tumors.
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. Similar to other IDH-mutated tumor types, IDH-mutated DDCHS also show elevated 2HG level, indicating that the oncometabolite activity of 2HG may contribute to DDCHS oncogenesis and progression.