Frequent Mutation of Isocitrate Dehydrogenase(IDH)1 and IDH2 in Cholangiocarcinoma Identified Through Broad-Based Tumor Genotyping
Open accessAbstract
Cancers of origin in the gallbladder and bile ducts are rarely curable with current modalities of cancer treatment. Our clinical application of broad-based mutational profiling for patients diagnosed with a gastrointestinal malignancy has led to the novel discovery of mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) in tumors from a subset of patients with cholangiocarcinoma. A total of 287 tumors from gastrointestinal cancer patients (biliary tract, colorectal, gastroesophageal, liver, pancreatic, and small intestine carcinoma) were tested during routine clinical evaluation for 130 site-specific mutations within 15 cancer genes. Mutations were identified within a number of genes, including KRAS (35%), TP53 (22%), PIK3CA (10%), BRAF (7%), APC (6%), NRAS (3%), AKT1 (1%), CTNNB1 (1%), and PTEN (1%). Although mutations in the metabolic enzyme IDH1 were rare in the other common gastrointestinal malignancies in this series (2%), they were found in three tumors (25%) of an initial series of 12 biliary tract carcinomas. To better define IDH1 and IDH2 mutational status, an additional 75 gallbladder and bile duct cancers were examined. Combining these cohorts of biliary cancers, mutations in IDH1 and IDH2 were found only in cholangiocarcinomas of intrahepatic origin (nine of 40, 23%) and in none of the 22 extrahepatic cholangiocarcinomas and none of the 25 gallbladder carcinomas. In an analysis of frozen tissue specimens, IDH1 mutation was associated with highly elevated tissue levels of the enzymatic product 2-hydroxyglutarate. Thus, IDH1 mutation is a molecular feature of cholangiocarcinomas of intrahepatic origin. These findings define a specific metabolic abnormality in this largely incurable type of gastrointestinal cancer and present a potentially new target for therapy.
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IDH1 and IDH2 mutations identified in low-grade glioma, chondrosarcoma, cholangiocarcinoma, and AML.
“IDH1 and IDH2 mutations have been identified in low-grade glioma, where they represent a likely initiator lesion, as well as in chondrosarcoma, cholangiocarcinoma, and acute myeloid leukemia (AML) (Balss et al., 2008; Borger et al., 2012; Cohen et al., 2013; Mardis et al., 2009; Parsons et al., 2008; Paschka et al., 2010).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Borger et al., 2012
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- Authors
- Borger, D. R., Tanabe, K. K., Fan, K. C., Lopez, H. U., Fantin, V. R., Straley, K. S., Schenkein, D. P., Hezel, A. F., Ancukiewicz, M., Liebman, H. M., Kwak, E. L., Clark, J. W., Ryan, D. P., Deshpande, V., Dias-Santagata, D., Ellisen, L. W., Zhu, A. X., & Iafrate, A. J.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital (US)
- Agios Pharmaceuticals (United States) (US)
- University of Rochester Medicine (US)
- Corresponding author
- Iafrate, A. John
- ORCID
- Venue
- The Oncologist
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-12-16
- Volume
- 17
- Issue
- 1
- Pages
- 72-79
- ISSN
- 1083-7159 (ISSN-L)
- 1549-490X
- PMC
- PMC3267826
- OpenAlex
- W2096796171
- Cited by
- 728
- References
- 45
- Citations by year
- 2026: 35 · 2025: 40 · 2024: 30 · 2023: 32 · 2022: 52 · 2021: 61 · 2020: 71 · 2019: 60 · 2018: 70 · 2017: 56 · 2016: 48 · 2015: 56 · 2014: 46 · 2013: 49 · 2012: 22
- FWCI
- 38.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Oncologist (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- MGH Cancer Center
- Topics
- Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
- Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- isocitrate dehydrogenase, IDH1 mutation, IDH2 mutation, cholangiocarcinoma, intrahepatic cholangiocarcinoma, gallbladder cancer, biliary tract cancer, 2-hydroxyglutarate, therapeutic target
- MeSH terms
- Adolescent, Adult, Bile Duct Neoplasms, Bile Ducts, Intrahepatic, Child, Female, Gallbladder Neoplasms, Genotype, Humans, Isocitrate Dehydrogenase, Male, Middle Aged, Mutation, Cholangiocarcinoma, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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