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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.

Author information

1
Department of Pharmacology, Gustave Roussy, Villejuif, France. Electronic address: julia.delahousse@gustaveroussy.fr.
2
Drug Development Department, Gustave Roussy, Department of Medical Oncology, Villejuif, France.
3
Department of Pharmacology, Gustave Roussy, Villejuif, France.
4
Service de biostatistique et d'épidémiologie, Gustave Roussy, Villejuif, France; Oncostat, INSERM U1018, CESP, Université Paris Sud, Gustave Roussy, Villejuif, France.
5
Department of Radiology, Gustave Roussy, Villejuif, France.
6
Department of Medical Biology and Pathology, Gustave Roussy, Villejuif, France.
7
Department of Gastrointestinal Oncology, Gustave Roussy, Villejuif, France.

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.

KEYWORDS:

2-hydroxyglutarate; Intrahepatic cholangiocarcinomas; Isocitrate dehydrogenase; Oncometabolite

PMID:
29274619
DOI:
10.1016/j.ejca.2017.11.024
[Indexed for MEDLINE]

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