JHU Intrahepatic Cholangiocarcinoma / Gallbladder Carcinoma WES 2013

Overview

The chol_jhu_2013 cohort was assembled by Jiao, Pawlik, Wood and colleagues at Johns Hopkins University and collaborating institutions to define the mutational landscape of intrahepatic cholangiocarcinoma (IHCH) and gallbladder carcinoma (GBC) by whole-exome sequencing. The study was the first large-scale genomic profiling effort in these biliary cancers and led to the discovery of recurrent inactivating mutations in the chromatin-remodeling genes BAP1, ARID1A, and PBRM1 as dominant drivers of IHCH, distinct from the TP53-dominated landscape of GBC.

Composition

  • Total samples: 80 (64 IHCH + 16 GBC across discovery and prevalence screens)
  • Discovery screen: 32 IHCH + 9 GBC (one GBC excluded — hypermutator), tumor + matched normal
  • Prevalence screen: 32 additional IHCH + 8 additional GBC
  • Key clinical fields: primary surgical resection specimens; IRB-approved collections at Johns Hopkins, MSKCC, Mayo Clinic, Fundeni Clinical Institute (Romania), and University Hospital Trust of Verona (Italy)
  • Reference genome: hg18 (exome discovery); hg19 (targeted prevalence screen)

Assays / panels (linked)

  • Whole-exome sequencing: Agilent SureSelect Paired-End v2.0 Human Exome + Illumina HiSeq 2000; mean coverage 130×; >90% of targeted bases ≥10× (discovery screen)
  • Targeted DNA sequencing: custom Ion AmpliSeq panel (17 candidate driver genes) on Ion Torrent PGM 318 chip; mean depth 1,276×; 88.9% of target bases ≥100× (prevalence screen)
  • Sanger sequencing: orthogonal validation of 50 mutations; 100% confirmed

Papers using this cohort

  • PMID:24185509 — Jiao et al., Nature Genetics 2013: discovery of BAP1/ARID1A/PBRM1 as recurrent IHCH drivers

Notable findings derived from this cohort

  • BAP1 inactivating mutations in 13/64 (20%) IHCH; first report of BAP1 alteration in a gastrointestinal cancer PMID:24185509
  • ARID1A mutated in 9/64 (14%) IHCH; PBRM1 in 8/64 (13%) IHCH and 4/16 (25%) GBC; at least one SWI/SNF chromatin-remodeling gene altered in 41% of combined IHCH cohort PMID:24185509
  • IDH1/IDH2 hotspot mutations in 20% of IHCH; associated with significantly worse survival (3-year OS 33% vs 81%, log-rank P=0.0034; Cox HR 7.37 after stage/age/sex adjustment) PMID:24185509
  • FGFR2 point mutations in 4/32 (13%) discovery-screen IHCH, complementing known FGFR2 gene fusions in cholangiocarcinoma PMID:24185509
  • TP53 was the dominant GBC alteration (5/8, 63% discovery screen; 44% combined GBC cohort), supporting genomically distinct biology between IHCH and GBC PMID:24185509
  • Used as a comparison dataset in the ICGC multi-omic CCA study; the TCGA ‘IDH’ and ‘METH3’ groups from this lineage of CCA studies map approximately to Cluster 4 of the four etiology-driven molecular subtypes PMID:28667006.

Sources

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