Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma

Kipp, Benjamin R.; Voss, Jesse S.; Kerr, Sarah E.; Fritcher, Emily G. Barr; Graham, Rondell P.; Zhang, Lizhi; Highsmith, W. Edward; Zhang, Jun; Roberts, Lewis R.; Gores, Gregory J.; Halling, Kevin C.

doi:10.1016/j.humpath.2011.12.007

Cited by 217 publications

(175 citation statements)

References 28 publications

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“…Moreover, D-2-HG acts as an oncometabolite in various human cancers harboring mutations in IDH1 or IDH2. Approximately 80% of secondary glioblastomas, 20% of AML, 50% of chondrosarcomas, and 10 to 20% of cholangiocarcinomas accumulate high levels of D-2-HG due to IDH1 or IDH2 mutations (49)(50)(51)(52)(53)(54). Furthermore, L-2-HG is elevated in clear cell renal cell carcinoma (ccRCC) due to reduced expression of the L2HGDH gene.…”

Section: Fig 6 Legend (Continued)mentioning

confidence: 99%

L2hgdh Deficiency Accumulates l-2-Hydroxyglutarate with Progressive Leukoencephalopathy and Neurodegeneration

Ma¹,

Sun²,

Jiang³

et al. 2017

Molecular and Cellular Biology

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L-2-Hydroxyglutarate aciduria (L-2-HGA) is an autosomal recessive neurometabolic disorder caused by a mutation in the L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. In this study, we generated L2hgdh knockout (KO) mice and observed a robust increase of L-2-hydroxyglutarate (L-2-HG) levels in multiple tissues. The highest levels of L-2-HG were observed in the brain and testis, with a corresponding increase in histone methylation in these tissues. L2hgdh KO mice exhibit white matter abnormalities, extensive gliosis, microglia-mediated neuroinflammation, and an expansion of oligodendrocyte progenitor cells (OPCs). Moreover, L2hgdh deficiency leads to impaired adult hippocampal neurogenesis and late-onset neurodegeneration in mouse brains. Our data provide in vivo evidence that L2hgdh mutation leads to L-2-HG accumulation, leukoencephalopathy, and neurodegeneration in mice, thereby offering new insights into the pathophysiology of L-2-HGA in humans.KEYWORDS L2HGDH, 2-HG, leukoencephalopathy, gliosis, neurodegeneration T he rare, autosomal recessive neurometabolic disorders D-2-hydroxyglutaric aciduria (D-2-HGA) and L-2-hydroxyglutaric aciduria (L-2-HGA) are characterized by the accumulation of D-2-hydroxyglutarate (D-2-HG) and L-2-hydroxyglutarate (L-2-HG), respectively, in body fluids. Genetic characterization has shown that 50% of the D-2-HGA population and the majority of L-2-HGA patients harbor pathogenic mutations in D2HGDH and L2HGDH genes, respectively (1-3). The other half of D-2-HGA patients have a gain-of-function mutation in isocitrate dehydrogenase 2 (IDH2) at the residue of R140 (R140Q), which leads to abnormally high accumulation of D-2-HG (4). Based on phenotypic severity in patients, D-2-HGA is classified as mild type I (D2HGDH mutation) and severe type II (IDH2 mutation) (4, 5). Of note, 2-HG concentrations are 2-to 8-fold higher for type II D-2-HGA than type I D-2-HGA patients (4, 6, 7), suggesting that

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Section: Fig 6 Legend (Continued)mentioning

confidence: 99%

L2hgdh Deficiency Accumulates l-2-Hydroxyglutarate with Progressive Leukoencephalopathy and Neurodegeneration

Ma¹,

Sun²,

Jiang³

et al. 2017

Molecular and Cellular Biology

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“…Amplicon-based panel sequencing, wgs, rna sequencing, and Sanger sequencing independently confirmed the presence of a somatic heterozygous mutation in the IDH1 gene, resulting in a p.Arg132Cys amino acid change. Such IDH1 mutations have been identified in up to a quarter of intrahepatic cholangiocarcinomas, but are rare elsewhere 19,20 .…”

Section: Resultsmentioning

confidence: 99%

Personalized Oncogenomics in the Management of Gastrointestinal Carcinomas—Early Experiences from a Pilot Study

et al. 2016

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“…In contrast, patients with cholangiocarcinoma and IDH1/2 mutations had shorter OS compared to those who are wild type (3-year survival of 33% in IDH mutants vs. 81% in IDH wild-type) (73). The frequency of these mutations ranges from 22-36% in ICCA and is associated with clear cell or poorly differentiated histology (74,75). Pre-clinical studies suggest that IDH mutations inhibit hepatocyte differentiation, induce proliferation of hepatic progenitors and ultimately leading to the development of premalignant lesions (76).…”

Section: Isocitrate Dehydrogenase (Idh) Inhibitorsmentioning

confidence: 99%

Therapeutic options for intrahepatic cholangiocarcinoma

Bupathi

Ahn

Bekaii‐Saab

2017

Hepatobiliary Surg. Nutr.

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Biliary tract cancer (BTC) is a heterogeneous group of cancers, which is composed of intrahepatic cholangiocarcinoma (ICCA), extrahepatic cholangiocarcinoma (ECCA), gallbladder cancers and ampullary carcinomas. While all anatomic subgroups are treated uniformly, our understanding about the pathogenesis has allowed us to reason that each group represents a clinically and genetically diverse disease.The majority of patients present with locally advanced or metastatic disease, where the standard treatment is combination systemic cytotoxic chemotherapy with gemcitabine and cisplatin. While most receive a clinical benefit from chemotherapy, patients eventually progress where no standardized therapies are available in the refractory setting. With the use of next generation sequencing, we have come to understand that ICCA is a diverse genomic disease with many actionable alterations that may serve as potential therapeutic targets. Further studies investigating the role of novel targeted agents (as a single agent or with combination chemotherapy) will hopefully provide additional treatment options for this highly lethal disease.

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Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma

Cited by 217 publications

References 28 publications

L2hgdh Deficiency Accumulates l-2-Hydroxyglutarate with Progressive Leukoencephalopathy and Neurodegeneration

L2hgdh Deficiency Accumulates l-2-Hydroxyglutarate with Progressive Leukoencephalopathy and Neurodegeneration

Personalized Oncogenomics in the Management of Gastrointestinal Carcinomas—Early Experiences from a Pilot Study

Therapeutic options for intrahepatic cholangiocarcinoma

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