PMID- 38015561
OWN - NLM
STAT- MEDLINE
DCOM- 20240306
LR  - 20240306
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 23
IP  - 3
DP  - 2024 Mar 4
TI  - Circulating Oncometabolite 2-hydroxyglutarate as a Potential Biomarker for 
      Isocitrate Dehydrogenase (IDH1/2) Mutant Cholangiocarcinoma.
PG  - 394-399
LID - 10.1158/1535-7163.MCT-23-0460 [doi]
AB  - Isocitrate dehydrogenase (IDH) enzymes catalyze the decarboxylation of isocitrate 
      to alpha-ketoglutarate (alphaKG). IDH1/2 mutations preferentially convert alphaKG to 
      R-2-hydroxyglutarate (R2HG), resulting in R2HG accumulation in tumor tissues. We 
      investigated circulating 2-hydroxyglutate (2HG) as potential biomarkers for 
      patients with IDH-mutant (IDHmt) cholangiocarcinoma (CCA). R2HG and 
      S-2-hydroxyglutarate (S2HG) levels in blood and tumor tissues were analyzed in a 
      discovery cohort of patients with IDHmt glioma and CCA. Results were validated in 
      cohorts of patients with CCA and clear-cell renal cell carcinoma. The R2HG/S2HG 
      ratio (rRS) was significantly elevated in tumor tissues, but not in blood for 
      patients with IDHmt glioma, while circulating rRS was elevated in patients with 
      IDHmt CCA. There were overlap distributions of circulating R2HG and total 2HG in 
      patients with both IDHmt and wild-type (IDHwt) CCA, while there was minimal 
      overlap in rRS values between patients with IDHmt and IDHwt CCA. Using the rRS 
      cut-off value of 1.5, the sensitivity of rRS was 90% and specificity was 96.8%. 
      Circulating rRS is significantly increased in patients with IDHmt CCA compare 
      with patients with IDHwt CCA. Circulating rRS is a sensitive and specific 
      surrogate biomarker for IDH1/2 mutations in CCA. It can potentially be used as a 
      tool for monitoring IDH-targeted therapy.
CI  - (c)2023 The Authors; Published by the American Association for Cancer Research.
FAU - Lee, Cha Len
AU  - Lee CL
AUID- ORCID: 0000-0002-3919-7539
AD  - Division of Medical Oncology and Haematology, Princess Margaret Cancer Center, 
      University Health Network, Toronto, Canada.
FAU - O'Kane, Grainne M
AU  - O'Kane GM
AUID- ORCID: 0000-0002-8690-403X
AD  - Department of Medical Oncology, Trinity St. James's Cancer Institute, Trinity 
      College Dublin, Dublin, Ireland.
FAU - Mason, Warren P
AU  - Mason WP
AUID- ORCID: 0000-0001-9107-2242
AD  - Division of Medical Oncology and Haematology, Princess Margaret Cancer Center, 
      University Health Network, Toronto, Canada.
AD  - MacFeeters Hamilton Center for Neuro-Oncology, University Health Network, 
      Toronto, Canada.
FAU - Zhang, Wen-Jiang
AU  - Zhang WJ
AUID- ORCID: 0009-0007-2519-8948
AD  - Division of Medical Oncology and Haematology, Princess Margaret Cancer Center, 
      University Health Network, Toronto, Canada.
FAU - Spiliopoulou, Pavlina
AU  - Spiliopoulou P
AUID- ORCID: 0000-0002-6486-6319
AD  - Division of Medical Oncology and Haematology, Princess Margaret Cancer Center, 
      University Health Network, Toronto, Canada.
FAU - Hansen, Aaron R
AU  - Hansen AR
AUID- ORCID: 0000-0002-2363-8707
AD  - Division of Cancer Services, Princess Alexandra Hospital, Brisbane, Queensland, 
      Australia.
FAU - Grant, Robert C
AU  - Grant RC
AUID- ORCID: 0000-0002-9821-0377
AD  - Division of Medical Oncology and Haematology, Princess Margaret Cancer Center, 
      University Health Network, Toronto, Canada.
FAU - Knox, Jennifer J
AU  - Knox JJ
AUID- ORCID: 0000-0003-3474-6647
AD  - Division of Medical Oncology and Haematology, Princess Margaret Cancer Center, 
      University Health Network, Toronto, Canada.
FAU - Stockley, Tracy L
AU  - Stockley TL
AUID- ORCID: 0000-0002-4476-9722
AD  - Advanced Molecular Diagnostic Laboratory, University Health Network, Toronto, 
      Canada.
FAU - Zadeh, Gelareh
AU  - Zadeh G
AUID- ORCID: 0000-0002-6637-4502
AD  - MacFeeters Hamilton Center for Neuro-Oncology, University Health Network, 
      Toronto, Canada.
FAU - Chen, Eric X
AU  - Chen EX
AUID- ORCID: 0000-0002-4581-8848
AD  - Division of Medical Oncology and Haematology, Princess Margaret Cancer Center, 
      University Health Network, Toronto, Canada.
LA  - eng
GR  - n/a/
PT  - Journal Article
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 2889-31-8 (alpha-hydroxyglutarate)
RN  - EC 1.1.1.41 (Isocitrate Dehydrogenase)
RN  - 0 (Biomarkers)
RN  - 0 (Ketoglutaric Acids)
RN  - EC 1.1.1.42. (IDH1 protein, human)
RN  - 0 (Glutarates)
SB  - IM
MH  - Humans
MH  - Isocitrate Dehydrogenase/genetics
MH  - Biomarkers
MH  - *Glioma/pathology
MH  - Mutation
MH  - Ketoglutaric Acids
MH  - *Cholangiocarcinoma/genetics
MH  - Bile Ducts, Intrahepatic/pathology
MH  - *Bile Duct Neoplasms/genetics
MH  - *Glutarates
PMC - PMC10911702
EDAT- 2023/11/28 12:42
MHDA- 2024/03/06 06:43
PMCR- 2024/03/04
CRDT- 2023/11/28 11:43
PHST- 2023/07/16 00:00 [received]
PHST- 2023/10/19 00:00 [revised]
PHST- 2023/11/22 00:00 [accepted]
PHST- 2024/03/06 06:43 [medline]
PHST- 2023/11/28 12:42 [pubmed]
PHST- 2023/11/28 11:43 [entrez]
PHST- 2024/03/04 00:00 [pmc-release]
AID - 731448 [pii]
AID - MCT-23-0460 [pii]
AID - 10.1158/1535-7163.MCT-23-0460 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2024 Mar 4;23(3):394-399. doi: 10.1158/1535-7163.MCT-23-0460.