Circulating oncometabolite D-2-hydroxyglutarate enantiomer is a surrogate marker of isocitrate dehydrogenase-mutated intrahepatic cholangiocarcinomas.

Abstract

Therapeutic resources are limited for advanced biliary tract cancers and prognosis remains poor. Somatic mutations in isocitrate dehydrogenase (IDH)1/2 gene are found in 5-36% of patients with intrahepatic cholangiocarcinoma (ICC). The mutant forms of IDH1/2 catalyse the non-reversible accumulation of 2-hydroxyglutarate (2HG). Increasing numbers of indirect or direct-targeted therapies are developed to IDH1/2 mutations and could be assisted by a routinely feasible, rapid and inexpensive serum 2HG measurement by liquid chromatography coupled to tandem mass spectrometry. By comparing eight patients with an IDH1/2-mutated ICC to nine patients with wild-type IDH1/2 ICC, we found significantly higher levels of 2HG in patients with IDH1/2 mutations versus the wild-type group (median, 10.9 vs. 0.8 μmol/L, p = 0.0037). D and L-2HG enantiomer levels significantly differed between the two groups with a higher level of D-2HG (p < 0.0001) in patients with IDH1/2 mutations. Accordingly, the D/L ratio was markedly higher in the patients with IDH1/2 mutations compared with the wild-type group (38.0 vs. 0.9 μmol/L, p < 0.0001). D-2HG measurement ensured 100% sensitivity and specificity at a cut-off of 0.6 μmol/L. D-2HG levels were correlated with tumour burden and tumour response to treatment with IDH-targeted therapies or indirect therapies. D-2HG serum level measurement by liquid chromatography coupled to tandem mass spectrometry is a sensitive, specific, precise (a coefficient of variation <10% and an accuracy >95%), fast (9 min run per sample) and inexpensive surrogate marker of IDH1/2 somatic mutation in ICC. Systematic measurement in patients with ICC may facilitate access to, and monitoring of, IDH-driven therapies.

• Authors: Julia Delahousse, Loic Verlingue, Sophie Broutin, Clémence Legoupil, Mehdi Touat, Ludovic Doucet, Samy Ammari, Ludovic Lacroix, Michel Ducreux, Jean-Yves Scoazec, David Malka, Angelo Paci, Antoine Hollebecque
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 90 Pg. 83-91 (02 2018) ISSN: 1879-0852 [Electronic] England
• PMID: 29274619 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Biomarkers, Tumor
• Glutarates
• alpha-hydroxyglutarate
• Isocitrate Dehydrogenase

Topics

• Adult
• Aged
• Bile Duct Neoplasms (blood, diagnosis, genetics)
• Biomarkers, Tumor (blood)
• Cholangiocarcinoma (blood, diagnosis, genetics)
• Female
• Glutarates (blood)
• Humans
• Isocitrate Dehydrogenase (genetics)
• Isomerism
• Male
• Middle Aged
• Mutation