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Highlights

• •

  Proteomic subgroups linked to iCCA patient survival, treatment, and molecular features

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  TP53, KRAS, FGFR2, IDH1/2, and BAP1 showed diverse pathways and therapeutic potential

• •

  Immunogenomics revealed the peptide immunogenicity derived from FGFR2 fusion

• •

  HKDC1 and SLC16A3 as significant prognostic indicators with biological functions

Summary

We performed proteogenomic label of intrahepatic cholangiocarcinoma (iCCA) using paired tumor and adjacent liver tissues from 262 patients. Integrated proteogenomic analyses prioritized genetic aberrations and revealed hallmarks of iCCA pathogenesis. Aflatoxin signature was associated with tumor initiation, proliferation, and immune suppression. Mutation-associated signaling profiles revealed that TP53 and KRAS co-mutations may contribute to iCCA metastasis via the integrin-FAK-SRC pathway. FGFR2 fusions activated the Rho GTPase pathway and could be a potential source of neoantigens. Proteomic profiling identified four patient subgroups (S1–S4) with subgroup-specific biomarkers. These proteomic subgroups had singled-out features in prognosis, genetic alterations, microenvironment dysregulation, tumor microbiota composition, and potential therapeutics. SLC16A3 and HKDC1 were further identified as potential prognostic biomarkers associated with metabolic reprogramming of iCCA cells. This study provides a valuable resource for researchers and clinicians to further identify molecular pathogenesis and therapeutic opportunities in iCCA.

Graphical abstract

Keywords

• intrahepatic cholangiocarcinoma
• proteogenomics
• molecular subgroups
• oncogenic drivers
• FGFR2 fusion
• prognostic biomarkers

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Article Info

Publication History

Published: December 30, 2021

Accepted: Dec 8, 2021

Received in revised class: July 19, 2021

Received: January 12, 2021

Identification

DOI: https://doi.org/10.1016/j.ccell.2021.12.006

Copyright

© 2021 Elsevier Inc.

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