title: Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping.
abstract: 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.
authors.affiliation: Division of Hematology-Oncology, Massachusetts General Hospital, Boston 02114-2698, USA
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Borger
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Tanabe
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Fan
authors.forename: Hector U
authors.initials: HU
authors.lastname: Lopez
authors.forename: Valeria R
authors.initials: VR
authors.lastname: Fantin
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Straley
authors.forename: David P
authors.initials: DP
authors.lastname: Schenkein
authors.forename: Aram F
authors.initials: AF
authors.lastname: Hezel
authors.forename: Marek
authors.initials: M
authors.lastname: Ancukiewicz
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Liebman
authors.forename: Eunice L
authors.initials: EL
authors.lastname: Kwak
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Clark
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.forename: Dora
authors.initials: D
authors.lastname: Dias-Santagata
authors.forename: Leif W
authors.initials: LW
authors.lastname: Ellisen
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
mesh_terms: D000293:Adolescent; D000328:Adult; D001650:Bile Duct Neoplasms / Q000201:enzymology / Q000235:genetics*; D001653:Bile Ducts, Intrahepatic / Q000473:pathology*; D002648:Child; D018281:Cholangiocarcinoma / Q000201:enzymology / Q000235:genetics*; D005260:Female; D005706:Gallbladder Neoplasms / Q000201:enzymology / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D055815:Young Adult
chemical_list: C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human