title: Mutations of isocitrate dehydrogenase 1 and 2 in intrahepatic cholangiocarcinoma.
abstract: OBJECTIVE
  Exome sequencing studies have recently expanded the genetic characterization of intrahepatic cholangiocarcinomas. Among a number of novel genes, isocitrate dehydrogenase (IDH) is recurrently mutated in intrahepatic cholangiocarcinomas. We review the effects of these mutations on several biochemical pathways, as well as potential changes to downstream signaling pathways.
  
  
  RESULTS
  Hotspot mutations in IDH isoforms 1 or 2 occur in approximately 15% of intrahepatic cholangiocarcinomas. These mutations result in elevated levels of an oncometabolite, 2-hydroxyglutarate, which is associated with higher DNA CpG methylation and altered histone methylation that accompany a block in cellular differentiation. Exploratory studies have suggested additional phenotypes associated with IDH1/2 mutations.
  
  
  CONCLUSIONS
  Tumors with IDH1 or IDH2 mutations may represent a distinct subtype of cholangiocarcinomas. Further studies are required to elucidate the exact role that mutant IDH1/2 and 2-hydroxyglutarate play in tumorigenesis, and what are the best strategies to target these tumor types.
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Grassian
authors.forename: Raymond
authors.initials: R
authors.lastname: Pagliarini
authors.forename: Derek Y
authors.initials: DY
authors.lastname: Chiang
mesh_terms: D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D002454:Cell Differentiation / Q000235:genetics; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D005977:Glutarates / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D009154:Mutation; D064828:Prolyl Hydroxylases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D064828:Prolyl Hydroxylases