Chronic Liver Disease Associated Cholangiocarcinoma: Genomic Insights and Precision Therapeutic Strategies

Authors

Kyoko Oura

Asahiro Morishita

Mai Nakahara

Tomoko Tadokoro

Koji Fujita

Joji Tani

Tsutomu Masaki

Hideki Kobara

Doi

10.3390/cancers17183052

PMID: 25526346 · DOI: 10.3390/cancers17183052 · Journal: Cancers (2025)

TL;DR

Narrative review synthesizing how chronic liver and biliary diseases (HBV, HCV, primary sclerosing cholangitis [PSC], primary biliary cholangitis [PBC], hepatolithiasis, metabolic dysfunction-associated steatotic liver disease [MASLD], alcohol-related liver disease [ALD], and liver fluke infection) shape the genomic landscape of cholangiocarcinoma (CCA). The authors compile reported frequencies of recurrent alterations across intrahepatic CCA (iCCA) and extrahepatic CCA (eCCA), summarize etiology-specific molecular signatures (e.g., TP53/KRAS/SMAD4/ERBB2 in PSC and liver-fluke-associated CCA; HBV DNA integration near TERT and MET in HBV-iCCA), and review the precision-therapy landscape including FGFR2 inhibitors (pemigatinib, infigratinib, futibatinib), the IDH1 inhibitor ivosidenib, HER2-directed regimens (trastuzumab + pertuzumab; trastuzumab-deruxtecan), the BRAF V600E combination of dabrafenib + trametinib, and TRK inhibitors (entrectinib, larotrectinib).

Cohort & data

  • Narrative review of published genomic and clinical literature. No new data were generated or analyzed.
  • Synthesizes cohorts cited in the literature, including a Chinese iCCA cohort of 103 patients (HBV-related), 41 iCCA patients (HBV DNA integration), 453 Japanese CCA patients (HCV antibody / FGFR fusions, OR 9.50), 186 PSC-CCA patients, 8/108/23 liver fluke–associated CCA series, and 38 hepatolithiasis-associated iCCA patients.
  • Cancers covered: IHCH, EHCH (perihilar and distal subtypes), and the cBioPortal umbrella code CHOL; also discusses overlap with HCC.

Key findings

  • Etiology shapes mutational landscape. PSC- and liver-fluke-associated CCA show distinct enrichment for TP53, KRAS, SMAD4, and ERBB2 alterations; HBV/HCV-related iCCA enrich for TP53, IDH1, PTEN, ARID1A, and (for HCV) FGFR2 rearrangements. MASLD and ALD remain genomically under-characterized.
  • KRAS mutation frequency is 24–27% in iCCA versus 37–46% in eCCA; G12D, G12V, and Q61H are the most common variants and G12/G13 alterations are associated with poor prognosis.
  • TP53 mutation frequency is 20–27% in iCCA and 35–68% in eCCA; eCCA tends to occur at higher frequency.
  • ARID1A mutation frequency is 18–23% in iCCA and 14% in eCCA. Loss of ARID1A in iCCA cells upregulates stemness markers including ALDH1A1; mechanistically, ARID1A represses ALDH1A1 transcription by recruiting HDAC1 and reducing H3K27 acetylation at the ALDH1A1 promoter. Co-occurring activating KRAS mutations and ARID1A deletions synergistically accelerate CCA development from cholangiocytes through suppression of the TGF-β/SMAD4 pathway.
  • CDKN2A/B alterations are seen in 15–27% of iCCA and 19% of eCCA; CDKN2A/B deletion emerges as an acquired-resistance mechanism in FGFR2 fusion-positive iCCA after FGFR inhibitor therapy, and is associated with shorter time to progression and poorer overall survival.
  • EGFR overexpression is reported in CCA at activating-alteration frequencies of 13.6–20%; EGFR-positive iCCA and eCCA have significantly lower 5-year overall survival than EGFR-negative cases (independent poor prognostic factor).
  • PIK3CA mutations occur in ~6% of iCCA and 3–7% of eCCA; cfDNA series report ~6.8% overall in advanced CCA.
  • BRAF V600E mutations appear in 3–7% of iCCA and nearly 0% of eCCA.
  • BRCA1/2 mutations occur in ~3–5% of iCCA/eCCA; relevant due to PARP inhibitor and platinum sensitivity.
  • SMAD4 mutations appear in ~4% of iCCA versus ~25% of eCCA; loss of SMAD4 protein in resected eCCA is associated with poor prognosis.
  • IDH1 mutations occur in 13–29% of iCCA and rarely in eCCA. Retrospective data show 14.5% prevalence in advanced iCCA with longer PFS for IDH1-mutant tumors versus wild-type under chemotherapy.
  • FGFR2 alterations (predominantly fusions/rearrangements, most commonly with BICC1 and TACC3) occur in 8–16% of iCCA and 0–2% of eCCA. Positive rates are 10–20% in Western iCCA cohorts vs. 7–8% in Japanese ICC. A Japanese multicenter study of 453 CCA patients (24 HCV-antibody positive) showed FGFR fusions strongly associated with HCV antibody positivity (OR 9.50); FGFR2 mutations in Asian iCCA also associate with female sex and younger age.
  • ERBB2 (HER2) alterations occur in 4–6% of iCCA and 3–20% of eCCA; ERBB2 overexpression is independently associated with shorter disease-free survival after curative resection.
  • HBV integration. In 41 iCCA patients including HBV-positive cases, HBV DNA integration is frequently observed in iCCA tumors and combined hepatocellular-cholangiocarcinoma, with recurrent insertions near TERT, MET, ALKBH5, and FAT2. HBV integration into the TERT promoter is frequent, mutually exclusive of TERT mutations, and associated with promoter hyperactivation.
  • PSC-associated CCA (n=186) shows TP53 (35.5%), KRAS (28.5%), CDKN2A (14.5%), SMAD4 (11.3%), with ERBB2 emerging as a potential therapeutic target. Sequential bile-duct dysplasia analyses show progressive accumulation from low-grade dysplasia (FGFR1, CDKN2A, SMAD4, EGFR, ERBB2) to high-grade dysplasia characterized by ERBB2 amplification (71%) and TP53 alterations (86%).
  • Liver-fluke-associated CCA. Whole-exome sequencing in 8 patients including Opisthorchis viverrini-associated CCA shows TP53 (44.4%), KRAS (16.7%), and SMAD4 (16.7%) mutations. In a 489-patient international study (23 fluke-positive), liver-fluke-positive cases showed recurrent ERBB2 amplifications and TP53 mutations; non-fluke-related CCA showed more frequent FGFR2 rearrangements and BAP1/IDH1/IDH2 alterations.
  • Hepatolithiasis-associated iCCA. In 38 iCCA patients (plus dysplasia/carcinoma-in-situ controls), KRAS mutations were detected in 48% of biliary intraepithelial neoplasia (BilIN) cases and 31.5% of iCCA cases; KRAS prevalence is highest in high-grade dysplasia, suggesting early-stage acquisition.
  • Small-duct vs. large-duct iCCA. Small-duct iCCA arising on chronic liver disease backgrounds is enriched for BAP1 and IDH1/IDH2 hotspot mutations and FGFR2 fusions with lower KRAS frequency; large-duct iCCA is enriched for TP53, KRAS, and TGF-β-pathway alterations (SMAD4, TGFBR2, FBXW7, MYC). Hotspot KRAS mutations occur more frequently in periductal-infiltrating CCA than in mass-forming subtype.
  • DDX1 is reported to be highly expressed in CCA with potential implications for prognosis and immune microenvironment modulation; functional validation in CCA remains limited.

Genes & alterations

  • KRAS — activating mutations (G12D, G12V, Q61H) in 24–27% iCCA and 37–46% eCCA; G12/G13 alterations predict poor prognosis. Synergizes with ARID1A loss to drive cholangiocarcinogenesis.
  • TP53 — mutations in 20–27% iCCA and 35–68% eCCA; HBsAg-positive iCCA preferentially harbors TP53 mutations.
  • ARID1A — loss-of-function mutations in 18–23% iCCA and 14% eCCA; represses ALDH1A1 via HDAC1/H3K27ac axis; loss enhances cancer stemness and correlates with poor prognosis. ARID1A-mutant tumors trend toward high MSI / high TMB and ICI sensitivity.
  • CDKN2A / CDKN2B — deletion/mutation in 15–27% iCCA and 19% eCCA; mediates acquired FGFR-inhibitor resistance in FGFR2 fusion-positive iCCA.
  • EGFR — activating alterations in 13.6–20% of CCA; overexpression is an independent poor-prognostic factor in iCCA and eCCA; bypass signaling via wild-type EGFR contributes to FGFR-inhibitor resistance.
  • PIK3CA — mutations in ~6% iCCA and 3–7% eCCA; ~6.8% in advanced cfDNA cohorts.
  • BRAF — V600E in 3–7% iCCA, near 0% in eCCA; actionable with dabrafenib + trametinib (ROAR phase II ORR ~47% in 43 CCA patients).
  • BRCA1 / BRCA2 — mutations in ~3–5% of CCA; rationale for PARP inhibitors and platinum agents.
  • SMAD4 — mutations in ~4% iCCA vs. ~25% eCCA; loss associated with poor prognosis after resection of eCCA.
  • IDH1 / IDH2 — hotspot mutations in 13–29% iCCA, rare in eCCA. IDH1-mutant iCCA benefits from ivosidenib (ClarIDHy phase III: ORR 2%, mPFS 6.9 vs. 2.7 months, mOS 10.3 vs. 7.5 months adjusted-crossover OS 5.1 months).
  • FGFR2 — fusions/rearrangements (BICC1, TACC3 partners) in 8–16% iCCA, 0–2% eCCA; targetable with pemigatinib, infigratinib, futibatinib. Secondary FGFR2 kinase-domain mutations at N550 and V565 emerge in ~60% of patients on reversible inhibitors but may remain sensitive to covalent futibatinib.
  • FGFR1 — alterations observed in low-grade dysplasia stage of PSC-associated CCA progression.
  • ERBB2 — amplification/overexpression in 4–6% iCCA and 3–20% eCCA; targetable with pertuzumab + trastuzumab (MyPathway ORR 23%) and trastuzumab-deruxtecan (HER2-positive CCA: ORR 22.0%, mPFS 4.6 months, mOS 7.0 months).
  • BAP1 — loss enriched in non-fluke-related CCA and small-duct iCCA.
  • PTEN — driver gene in HBV-associated iCCA cohort.
  • TERT — promoter hyperactivation via HBV DNA integration (mutually exclusive of TERT promoter mutations).
  • MET, ALKBH5, FAT2 — recurrent HBV integration sites near these oncogenes in iCCA.
  • NTRK1 / NTRK2 / NTRK3 — fusions reported in ~0.2% of CCA overall, up to 3.6% of iCCA; targetable with entrectinib and larotrectinib.
  • DDX1 — highly expressed in CCA with prognostic and immune-microenvironment implications (functional validation pending).
  • ALDH1A1 — stemness marker derepressed upon ARID1A loss in iCCA.
  • TGFBR2, FBXW7, MYC — enriched among large-duct-type iCCA.

Clinical implications

  • Treatment. Standard first-line for advanced CCA is gemcitabine + cisplatin, with the addition of durvalumab (immune checkpoint inhibitor) showing incremental benefit. Targeted therapies are typically positioned after first-line failure; molecular profiling at diagnosis is recommended (ESMO guidelines).
    • FGFR2 fusion/rearrangement: pemigatinib (FIGHT-202 phase II: ORR 35.5%, mPFS 6.9 mo, mOS 21.1 mo); infigratinib (phase III negative vs. gem-cis but consistent 37.9% ORR); futibatinib (FOENIX-CCA2 phase II: ORR 42.0%, mPFS 9.0 mo, mOS 21.7 mo; covalent irreversible inhibitor with activity against on-target resistance mutations).
    • IDH1 mutation: ivosidenib (ClarIDHy phase III: significant PFS/OS benefit vs. placebo).
    • HER2 (ERBB2) alteration: pertuzumab + trastuzumab (MyPathway phase IIa basket ORR 23%); trastuzumab-deruxtecan (basket phase II across 7 cohorts: ORR 37.1% overall, 22.0% in 41 CCA patients; mPFS 4.6 mo, mOS 7.0 mo in CCA; risk of interstitial pneumonitis).
    • BRAF V600E: dabrafenib + trametinib (ROAR basket phase II: ORR ~47% in 43 CCA patients, mPFS ~9 mo, mOS ~14 mo).
    • NTRK fusion: entrectinib (pooled 121 NTRK-positive: ORR 61.2%, mPFS 13.8 mo, mOS 33.8 mo); larotrectinib (75% ORR in 55 NTRK-fusion patients including 2 CCA; treatment-naïve TRK-fusion update: ORR 77%, mPFS 59 mo).
    • BRCA1/2 mutation: PARP inhibitor and platinum sensitivity expected; ~3–5% of CCA cases.
  • Prognosis. EGFR overexpression, ERBB2 overexpression, SMAD4 loss, CDKN2A/B deletion, and KRAS G12/G13 mutations are independent poor-prognostic markers in CCA. IDH1 mutations may confer better tumor biology and longer PFS.
  • Biomarkers / screening. FGFR2 mutations in Asia associate with HCV infection, female sex, and younger age — supports targeted screening of these subgroups. Bile-based liquid biopsy (CDO1, SEPT9, vimentin methylation; NGS of bile-duct brush specimens) may improve early detection of CCA in PSC. cfDNA monitoring is feasible for KRAS, PIK3CA, and HER2 dynamics.
  • Resistance. FGFR inhibitor resistance arises from secondary FGFR2 kinase-domain mutations (N550, V565), MAPK-pathway bypass, wild-type EGFR/ERBB compensatory signaling, and TP53 co-mutations (primary resistance). Co-inhibition of EGFR enhances FGFR-inhibitor response in preclinical models. IDH inhibitor resistance can involve secondary IDH mutations and isoform switching (IDH1→IDH2). HER2 resistance to neratinib was associated with reduction in HER2 copy number and decreased S310F variant allele frequency in paired tumor/cfDNA analyses.

Limitations & open questions

  • This is a narrative review, not a systematic review or meta-analysis; literature selection is not exhaustive.
  • The authors explicitly note inconsistencies among published studies in epidemiologic associations and genomic-alteration prevalence, attributing them to differences in study design, cohort size, demographics, regional etiologies, and methodology.
  • MASLD and ALD remain genomically under-characterized for CCA — large cohorts with stratification by these etiologies are needed.
  • The optimal sequencing of targeted therapy vs. chemo-immunotherapy is unresolved; no prospective head-to-head trials exist.
  • Mechanisms of IDH-inhibitor resistance in CCA are poorly characterized compared with AML.
  • Liquid biopsy sensitivity in CCA varies with tumor burden and anatomical site; should complement, not replace, tissue analysis.

Citations from this paper used in the wiki

  • “KRAS mutations are relatively common in CCA, with a reported frequency of 24–27% in iCCA … and 37–46% in eCCA … alterations at G12/G13 are strongly associated with poor prognosis.” (Table 1; Section 3.1)
  • “The frequency of TP53 mutations is generally high in CCA but has been reported to be 20–27% in iCCA … and 35–68% in eCCA.” (Section 3.1)
  • “Its frequency in CCA has been reported to be 18–23% in iCCA … and 14% in eCCA … co-occurrence of activating KRAS mutations and ARID1A deletions has been shown to synergistically accelerate cholangiocarcinoma development from cholangiocytes.” (Section 3.1, on ARID1A)
  • “CDKN2A/B gene mutations are observed in 15–27% of iCCA cases … and 19% of eCCA cases … in patients with FGFR2 fusion-positive iCCA, the CDKN2A/B deletion emerged after the development of acquired resistance to FGFR inhibitors.” (Section 3.1)
  • “FGFR2 mutations have been reported in 8–16% of iCCA and 0–2% of eCCA cases … FGFR fusions or rearrangements were strongly associated with HCV antibody positivity, with an odds ratio of 9.50.” (Sections 3.2 and 4.1)
  • “Genomic analyses in a large-scale multicenter study of 186 patients revealed frequent typical alterations of eCCA, including TP53 (35.5%), KRAS (28.5%), CDKN2A (14.5%), and SMAD4 (11.3%), as well as potential therapeutic targets such as ERBB2.” (Section 4.2, PSC)
  • “Pemigatinib … ORR of 35.5% in CCA patients with FGFR2 fusion or rearrangement … median PFS … 6.9 months, and median OS was 21.1 months.” (Section 5.1)
  • “Futibatinib … ORR of 42.0%, a median PFS of 9.0 months, and a median OS of 21.7 months.” (Section 5.1)
  • “Ivosidenib … ORR for ivosidenib was 2%, … DCR was 53%. … median PFS in the ivosidenib group was 6.9 months, compared with 2.7 months in the placebo group … final median OS … 10.3 months in the ivosidenib group, compared with 7.5 months in the placebo group.” (Section 5.2)
  • “ROAR basket trial (a Phase II study) … Among 43 CCA patients, the ORR assessed by independent central review was 47% … Median PFS and OS were approximately 9 months and 14 months, respectively.” (Section 5.4, BRAF V600E)
  • “Approximately 60% of patients develop secondary FGFR2 kinase domain mutations—most commonly at N550 and V565 residues—which limit the efficacy of reversible inhibitors but may remain sensitive to irreversible inhibitors such as futibatinib.” (Section 6, resistance)

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