Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Farshad Farshidfar
  • Siyuan Zheng
  • Marie-Claude Gingras
  • Yulia Newton
  • Juliann Shih
  • A Gordon Robertson
  • Toshinori Hinoue
  • Katherine A Hoadley
  • Ewan A Gibb
  • Jason Roszik
  • Kyle R Covington
  • Chia-Chin Wu
  • Eve Shinbrot
  • Nicolas Stransky
  • Apurva Hegde
  • Ju Dong Yang
  • Ed Reznik
  • Sara Sadeghi
  • Chandra Sekhar Pedamallu
  • Akinyemi I Ojesina
  • Julian M Hess
  • J Todd Auman
  • Suhn Kyong Rhie
  • Reanne Bowlby
  • Mitesh J Borad
  • Andrew X Zhu
  • Josh M Stuart
  • Chris Sander
  • Rehan Akbani
  • Andrew D Cherniack
  • Vikram Deshpande
  • Taofic Mounajjed
  • Wai Chin Foo
  • Michael S Torbenson
  • David E Kleiner
  • Peter W Laird
  • David A Wheeler
  • Autumn J McRee
  • Oliver F Bathe
  • Andersen, Jesper Bøje
  • Nabeel Bardeesy
  • Lewis R Roberts
  • Lawrence N Kwong
  • Cancer Genome Atlas Network

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.

OriginalsprogEngelsk
TidsskriftCell Reports
Vol/bind18
Udgave nummer11
Sider (fra-til)2780-2794
Antal sider15
ISSN2211-1247
DOI
StatusUdgivet - 14 mar. 2017

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