- •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.
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.
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)
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- Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution.Ann Surg. 2007; 245: 755-762
- Cancer statistics, 2015.CA Cancer J Clin. 2015; 65: 5-29
- Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection.Ann Surg. 2008; 248: 84-96
- Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials.Br J Cancer. 2007; 96: 896-902
- Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.N. Engl J Med. 2010; 362: 1273-1281
- Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study.J Clin Oncol Official J Am Soc Clin Oncol. 2010; 28: 4581-4586
- Matching genomic molecular aberrations with molecular targeted agents: are biliary tract cancers an ideal playground?.Eur J cancer. 2017; 81: 161-173
- IDH1 and IDH2 mutations in gliomas.N. Engl J Med. 2009; 360: 765-773
- IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study.J Clin Oncol Official J Am Soc Clin Oncol. 2010; 28: 2348-2355
- IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours.J Pathol. 2011; 224: 334-343
- Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma.Hum Pathol. 2012; 43: 1552-1558
- Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping.Oncol. 2012; 17: 72-79
- Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.Nature. 2009; 462: 739-744
- Serum 2-hydroxyglutarate production in IDH1- and IDH2-mutated de novo acute myeloid leukemia: a study by the Acute Leukemia French Association group.J Clin Oncol Official J Am Soc Clin Oncol. 2014; 32: 297-305
- Quantitation of isocitrate dehydrogenase (IDH)-induced D and L enantiomers of 2-hydroxyglutaric acid in biological fluids by a fully validated liquid tandem mass spectrometry method, suitable for clinical applications.J Chromatogr B Anal Technol Biomed Life Sci. 2016; 1022: 290-297
- Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity.Nat Commun. 2015; 6: 6120
- Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.Expert Rev Gastroenterol Hepatol. 2010; 4: 395-397
- Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups.Oncotarget. 2014; 5: 2839-2852
- Molecular characterization of gallbladder cancer using somatic mutation profiling.Hum Pathol. 2014; 45: 701-708
- Molecular profiling of cholangiocarcinoma shows potential for targeted therapy treatment decisions.Hum Pathol. 2013; 44: 1216-1222
- New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing.Oncol. 2014; 19: 235-242
- Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas.Nat Genet. 2013; 45: 1470-1473
- Circulating oncometabolite 2-hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase-mutant intrahepatic cholangiocarcinoma.Clin Cancer Res Official J Am Assoc Cancer Res. 2014; 20: 1884-1890
- Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas.Oncogene. 2013; 32: 3091-3100
- Mutational landscape of intrahepatic cholangiocarcinoma.Nat Commun. 2014; 5: 5696
- Exome sequencing of liver fluke-associated cholangiocarcinoma.Nat Genet. 2012; 44: 690-693
- Comparison of gene expression profiles between Opisthorchis viverrini and non-Opisthorchis viverrini associated human intrahepatic cholangiocarcinoma.Hepatology. 2006; 44: 1025-1038
- High-throughput genomics and clinical outcome in hard-to-treat advanced cancers: results of the MOSCATO 01 trial.Cancer Discov. 2017; 7: 586-595
- Factors associated with success of image-guided tumour biopsies: results from a prospective molecular triage study (MOSCATO-01).Eur J Cancer. 2016; 59: 79-89
- Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial.Lancet Oncol. 2015; 16: 1324-1334
- Molecular profiling of advanced solid tumors and patient outcomes with genotype-matched clinical trials: the Princess Margaret IMPACT/COMPACT trial.Genome Med. 2016; 8: 109
- 2-Hydroxyglutarate is not a metabolite; D-2-hydroxyglutarate and L-2-hydroxyglutarate are!.Proc Natl Acad Sci U S A. 2013; 110: E4939
- Discovery of the first potent inhibitors of mutant IDH1 that lower tumor 2-HG in vivo.ACS Med Chem Lett. 2012; 3: 850-855
- Inhibition of cancer-associated mutant isocitrate dehydrogenases by 2-thiohydantoin compounds.J Med Chem. 2015; 58: 6899-6908
- Hypoxia induces production of L-2-hydroxyglutarate.Cell Metab. 2015; 22: 304-311
- O11.3 * Targeting isocitrate dehydrogenase (IDH)1 and IDH2 mutations Clinical results in advanced hematologic malignancies.Ann Oncol. 2015; 26 (ii15-ii)
- 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity.Sci Transl Med. 2017; 9
- Isocitrate dehydrogenase mutations confer dasatinib hypersensitivity and SRC dependence in intrahepatic cholangiocarcinoma.Cancer Discov. 2016; 6: 727-739
Published online: December 21, 2017
Accepted: November 22, 2017
Received: November 16, 2017
© 2017 Elsevier Ltd. All rights reserved.