Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma

Liangqing Dong, Dayun Lu, Ran Chen, Youpei Lin, Hongwen Zhu, Zhou Zhang, Shangli Cai, Peng Cui, Guohe Song, Dongning Rao, Xinpei Yi, Yingcheng Wu, Nixue Song, Fen Liu, Yunhao Zou, Shu Zhang, Xiaoming Zhang, Xiaoying Wang, Shuangjian Qiu, Jian ZhouShisheng Wang, Xu Zhang, Yongyong Shi, Daniel Figeys, Li Ding, Pei Wang, Bing Zhang, Henry Rodriguez, Qiang Gao, Daming Gao, Hu Zhou, Jia Fan

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

We performed proteogenomic characterization 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 distinct 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.

Original languageEnglish
Pages (from-to)70-87.e15
JournalCancer Cell
Volume40
Issue number1
DOIs
StatePublished - Jan 10 2022

Keywords

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

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