Intrahepatic Cholangiocarcinoma (IHCH)

Overview

Intrahepatic cholangiocarcinoma, a primary liver cancer arising from intrahepatic bile duct epithelium.

Cohorts in the corpus

  • hcc_msk_2024 — 527 IHC tumors classified by the “hidden-genome” classifier, within a larger MSK biliary/HCC cohort of 1,370 MSK-IMPACT-sequenced patients (2003–2022) PMID:38864854.

Recurrent alterations

  • 410 IHC (78%) had >50% genetic homology with EHC/GBC; 122 (23%) exceeded >90% homology (“biliary-class”) characterized by KRAS, SMAD4, and CDKN2A loss PMID:38864854.
  • 117 IHC (22%) had >50% genetic homology with HCC; 30 (5.7%) exceeded >90% homology (“HCC-class”) characterized by TERT alterations PMID:38864854.
  • Classifier predicted OS independently of FGFR2 and IDH1 alterations PMID:38864854.
  • Whole-exome sequencing of 64 IHCH (32 discovery + 32 prevalence screen) identified recurrent inactivating mutations in chromatin-remodeling genes BAP1 (20%), ARID1A (14%), and PBRM1 (13%); at least one of these was altered in 41% of tumors. IDH1/IDH2 hotspot mutations occurred in 20% of IHCH and were associated with significantly worse 3-year survival (33% vs 81%; HR 7.37, P=0.037 after adjustment). PMID:24185509
  • Narrative review of etiology-driven genomic landscape of iCCA: IDH1 mutations in 13-29%, FGFR2 fusions/rearrangements in 8-16% (0-2% in eCCA), KRAS in 24-27%, TP53 in 20-27%, ARID1A in 18-23%, CDKN2A/B in 15-27%; etiology-specific profiles include HBV DNA integration near TERT and MET, HCV association with FGFR fusions (OR 9.50), and PSC association with TP53/KRAS/SMAD4 PMID:25526346.
  • Review covers intrahepatic cholangiocarcinoma (iCCA) specifically: IDH1/IDH2 mutations drive 2-HG accumulation suppressing BA synthesis genes; FGFR2 fusions/rearrangements are recurrent; BA-active iCCA subtype (defined by single-cell RNA-seq) shows shorter OS and immunotherapy resistance, with SLCO1B3 and CEACAM1 as prognostic markers. PMID:25608663
  • ICGC profiling of 489 CCAs showed IHCH (intrahepatic) is enriched for Clusters 3 and 4 (fluke-negative): IDH1/IDH2 mutations (31.6% in Cluster 4), BAP1 inactivation, FGFR2 rearrangements, and high copy-number alterations with PD-1/PD-L2 upregulation; BAP1 and KRAS are significantly more frequent in intrahepatic CCAs (q<0.1). PMID:28667006

Subtypes

  • Biliary-class IHC vs HCC-class IHC via hidden-genome classifier; large-duct IHC (n=28) almost exclusively biliary-class (27/28); HCC-class tumors mostly small-duct IHC (64%, p=0.02) PMID:38864854.

Therapeutic landscape

  • Median OS, unresectable: biliary- vs non-biliary-class 1.0 vs 1.8 years; resectable: 2.4 vs 5.1 years PMID:38864854.
  • Authors propose the classifier to stratify patients in future IHC trials independent of FGFR2/IDH1-directed therapy PMID:38864854.

Sources

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