Highlights
- •Somatic mutations in isocitrate dehydrogenase (IDH) are found in patients with intrahepatic cholangiocarcinoma.
- •Production of D-2-hydroxyglutarate enantiomers (2HG) is increased in the serum of patient with IDH mutation.
- •D-2HG measurement and D/L-2HG ratio are a reproducible and quick tools to predict the IDH mutation.
- •Systematic measurement may facilitate access to IDH-driven therapies.
- •D-2HG measurement and D/L-2HG ratio are a tool for monitoring treatment.
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
Abbreviations:
IDH (isocitrate dehydrogenase), 2HG (2-hydroxyglutarate), BTCs (biliary tract cancers), ICCs (intrahepatic cholangiocarcinomas), 2-OG (2-oxoglutarate), D (dextrogyre), L (laevogyre), LC-MS/MS (liquid chromatography coupled to tandem mass spectrometry), NGS (next generation sequencing)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: December 21, 2017
Accepted:
November 22,
2017
Received:
November 16,
2017
Identification
Copyright
© 2017 Elsevier Ltd. All rights reserved.
