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Eur J Cancer. 2018 Feb;90:83-91. doi: 10.1016/j.ejca.2017.11.024. Epub 2018 Jan 4.

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

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Department of Pharmacology, Gustave Roussy, Villejuif, France. Electronic address:
Drug Development Department, Gustave Roussy, Department of Medical Oncology, Villejuif, France.
Department of Pharmacology, Gustave Roussy, Villejuif, France.
Service de biostatistique et d'épidémiologie, Gustave Roussy, Villejuif, France; Oncostat, INSERM U1018, CESP, Université Paris Sud, Gustave Roussy, Villejuif, France.
Department of Radiology, Gustave Roussy, Villejuif, France.
Department of Medical Biology and Pathology, Gustave Roussy, Villejuif, France.
Department of Gastrointestinal Oncology, Gustave Roussy, Villejuif, France.


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.


2-hydroxyglutarate; Intrahepatic cholangiocarcinomas; Isocitrate dehydrogenase; Oncometabolite

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