Circulating oncometabolite 2-hydroxyglutarate (2HG) as a potential biomarker for isocitrate dehydrogenase (IDH1/2) mutant cholangiocarcinoma

Lee, C. L. et al. (2023) Circulating oncometabolite 2-hydroxyglutarate (2HG) as a potential biomarker for isocitrate dehydrogenase (IDH1/2) mutant cholangiocarcinoma. Molecular Cancer Therapeutics, (doi: 10.1158/1535-7163.mct-23-0460) (PMID:38015561) (Early Online Publication)

Abstract

Isocitrate dehydrogenase (IDH) enzymes catalyze the decarboxylation of isocitrate to alpha-ketoglutarate. IDH1/2 mutations preferentially convert αKG to R-2-hydroxyglutarate (R2HG), resulting in R2HG accumulation in tumor tissues. We investigated circulating 2-hydroxyglutate (2HG) as potential biomarkers for patients with IDH-mutant (IDHmt) cholangiocarcinoma (CCA). R2HG and S-2-hydroxyglutarate (S2HG) levels in blood and tumor tissues were analyzed in a discovery cohort of IDHmt glioma and CCA patients. Results were validated in cohorts of CCA and clear cell renal cell carcinoma (ccRCC) patients. The R2HG/S2HG ratio (rRS) was significantly elevated in tumor tissues, but not in blood for IDHmt glioma patients, while circulating rRS was elevated in IDHmt CCA patients. There were overlap distributions of circulating R2HG and total 2HG (t2HG) in both IDHmt and wild-type (IDHwt) CCA patients, while there was minimal overlap in rRS values between IDHmt and IDHwt CCA patients. Using the rRS cut-off value of 1.5, the sensitivity of rRS was 90% and specificity was 96.8%. Circulating rRS is significantly increased in IDHmt CCA patients compare to IDHwt CCA patients. Circulating rRS is a sensitive and specific surrogate biomarker for IDH1/2 mutations in CCA. It can potentially be used as a tool for monitoring IDH-targeted therapy.

• Item Type: Articles
• Additional Information: Funding is provided through the generous support of the Princess Margaret Cancer Center Foundation.
• Status: Early Online Publication
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Spiliopoulou, Dr Pavlina
• Authors: Lee, C. L., O'Kane, G. M., Mason, W. P., Zhang, W.-J., Spiliopoulou, P., Hansen, A. R., Grant, R. C., Knox, J. J., Stockley, T. L., Zadeh, G., and Chen, E. X.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Molecular Cancer Therapeutics
• Publisher: American Association for Cancer Research (AACR)
• ISSN: 1535-7163
• ISSN (Online): 1538-8514
• Published Online: 01 January 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Molecular Cancer Therapeutics 2023
• Publisher Policy: Reproduced under a Creative Commons licence

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