Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma

Abstract Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analyzed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined 4 CCA clusters—fluke-positive CCAs (clusters 1/2) are enriched in ERBB2 amplifications and TP53 mutations; conversely, fluke-negative CCAs (clusters 3/4) exhibit high copy-number alterations and PD-1/PD-L2 expression, or epigenetic mutations (IDH1/2, BAP1) and FGFR/PRKA-related gene rearrangements. Whole-genome analysis highlighted FGFR2 3′ untranslated region deletion as a mechanism of FGFR2…

• JA
  Japan Agency for Medical Research and Development

  Award: 15ck0106094h0002
• DM
  Duke-NUS Medical School
• FI
  Fondazione Italiana per la ricerca sulle Malattie del Pancreas
• NR
  National Research Foundation
• NU
  National University of Singapore
• NR
  National Research Foundation Singapore
• SG
  Singapore General Hospital
• NN
  National Natural Science Foundation of China

  Award: NSFC81372825
• AI
  Associazione Italiana per la Ricerca sul Cancro

  Award: n. 12182
• GI
  Genome Institute of Singapore
• NI
  National Institutes of Health

  Award: P01CA142538
• MR
  Medical Research Council
• NM
  National Medical Research Council

  Awards: NMRC/STaR/0026/2015, STaR/0026/2015, NMRC/CG/012/2013, NMRC/CIRG/1422/2015, 0026/2015, CIRG/1422/2015, NMRC/STaR/0024/2014
• NC
  National Cancer Institute

  Award: P01CA142538