A Novel Approach to Quantify Heterogeneity of Intrahepatic Cholangiocarcinoma: the Hidden-Genome Classifier

Authors

Yi Song

Thomas Boerner

Esther Drill

Paul Shin

Sandeep Kumar

Carlie Sigel

Andrea Cercek

Nancy Kemeny

Ghassan Abou-Alfa

Christine Iacobuzio-Donahue

Darren Cowzer

Nikolaus Schultz

Henry Walch

Vinod Balachandran

Bas Groot Koerkamp

Peter Kingham

Kevin Soares

Alice Wei

Michael D’Angelica

Jeffrey Drebin

Rohit Chandwani

James Harding

William Jarnagin

Doi

10.1158/1078-0432.CCR-24-0657

PMID: 38864854 · DOI: 10.1158/1078-0432.CCR-24-0657 · Journal: Clinical Cancer Research (2024)

TL;DR

Song et al. applied a supervised machine-learning “hidden-genome” classifier to 527 intrahepatic cholangiocarcinomas (IHC) sequenced by MSK-IMPACT, scoring each tumor’s genetic similarity to extrahepatic cholangiocarcinoma/gallbladder cancer (EHC/GBC) versus hepatocellular carcinoma (HCC). IHC genetics form a spectrum: “biliary-class” IHC (>90% EHC/GBC homology, 23%) is KRAS/SMAD4/CDKN2A-driven and has markedly worse overall survival than “HCC-class” IHC (>90% HCC homology, 5.7%, TERT-driven), and the classifier predicts OS independently of FGFR2 and IDH1 alterations and outperforms histologic subtyping PMID:38864854.

Cohort & data

  • 1,370 patients with histologically confirmed biliary tract cancer, HCC, or biphenotypic IHC/HCC tumors at MSK, sequenced 2003–2022 on MSK-IMPACT (panels 341/410/468/505; 341 common genes used).
  • 527 IHCH classified; trained against EHCH, GBC, and HCC reference classes.
  • Dataset: hcc_msk_2024.

Key findings

  • 410 IHC (78%) had >50% genetic homology with EHC/GBC; 122 (23%) exceeded >90% homology and were labeled “biliary-class” PMID:38864854.
  • 117 IHC (22%) had >50% genetic homology with HCC; 30 (5.7%) exceeded >90% homology and were labeled “HCC-class” PMID:38864854.
  • Biliary-class IHC was characterized by alterations in KRAS, SMAD4, and CDKN2A loss; HCC-class was characterized by TERT alterations PMID:38864854.
  • Median OS, unresectable disease: biliary- vs. non-biliary-class = 1.0 year (95% CI 0.77–1.5) vs. 1.8 years (95% CI 1.6–2.0) PMID:38864854.
  • Median OS, resectable disease: biliary- vs. non-biliary-class = 2.4 years (95% CI 2.1–NR) vs. 5.1 years (95% CI 4.8–6.9) PMID:38864854.
  • Large-duct IHC (n=28) was almost exclusively biliary-class (n=27); HCC-class tumors were mostly small-duct IHC (64%, p=0.02) PMID:38864854.
  • The hidden-genome classifier predicted OS independently of FGFR2 and IDH1 alterations; histologic subtype did not predict OS PMID:38864854.

Genes & alterations

  • KRAS — enriched in biliary-class IHC; discriminative of EHC/GBC-like genetics.
  • SMAD4 — enriched in biliary-class IHC.
  • CDKN2A — loss enriched in biliary-class IHC.
  • TERT — alterations characterize HCC-class IHC.
  • FGFR2 — actionable driver; classifier adds prognostic information independent of FGFR2 status.
  • IDH1 — actionable driver; classifier prognostic independent of IDH1 status.

Clinical implications

  • The hidden-genome classifier stratifies IHC into prognostic subgroups (biliary- vs. HCC-class) with large OS differences in both resectable and unresectable disease, and does so independently of the established FGFR2/IDH1 targetable alterations PMID:38864854.
  • Authors propose using the classifier to stratify patients in future IHC clinical trials and to help explain heterogeneous treatment responses in IHC PMID:38864854.

Limitations & open questions

  • Single-institution retrospective MSK cohort; restricted to the 341 genes common across MSK-IMPACT panel versions.
  • Classifier was trained on EHC/GBC vs. HCC reference classes only; intermediate/mixed IHCs (roughly half the cohort) are not cleanly captured by the >90% homology thresholds.
  • Prospective validation and linkage to specific therapy responses (e.g., gemcitabine/cisplatin, FGFR/IDH1 inhibitors, immunotherapy) remain open.

Citations from this paper used in the wiki

  • “410 IHC (78%) had >50% genetic homology with EHC/GBC; 122 (23%) had >90% homology (‘biliary-class’), characterized by alterations of KRAS, SMAD4, and CDKN2A loss.” (Abstract)
  • “117 IHC (22%) had >50% genetic homology with HCC; 30 (5.7%) had >90% homology (‘HCC-class’), characterized by TERT alterations.” (Abstract)
  • “The hidden-genomic classifier predicted OS independent of FGFR2 and IDH1 alterations. By contrast, the histology subtype did not predict OS.” (Abstract)

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