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 Zhou; Shisheng Wang; Xu Zhang; Yongyong Shi; Daniel Figeys; Li Ding; Pei Wang; Bing Zhang; Henry Rodriguez; Qiang Gao; Daming Gao; Hu Zhou; Jia Fan

doi:10.1016/j.ccell.2021.12.006

Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma

Cancer Cell. 2022 Jan 10;40(1):70-87.e15. doi: 10.1016/j.ccell.2021.12.006. Epub 2021 Dec 30.

Authors

Liangqing Dong¹, Dayun Lu², Ran Chen³, Youpei Lin¹, Hongwen Zhu⁴, Zhou Zhang⁵, Shangli Cai⁵, Peng Cui⁵, Guohe Song¹, Dongning Rao¹, Xinpei Yi⁶, Yingcheng Wu¹, Nixue Song², Fen Liu³, Yunhao Zou³, Shu Zhang¹, Xiaoming Zhang⁷, Xiaoying Wang¹, Shuangjian Qiu¹, Jian Zhou⁸, Shisheng Wang⁹, Xu Zhang¹⁰, Yongyong Shi¹¹, Daniel Figeys¹⁰, Li Ding¹², Pei Wang¹³, Bing Zhang⁶, Henry Rodriguez¹⁴, Qiang Gao¹⁵, Daming Gao¹⁶, Hu Zhou¹⁷, Jia Fan¹⁸

Affiliations

¹ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China.
² Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, Number 19A Yuquan Road, Beijing 100049, China.
³ University of Chinese Academy of Sciences, Number 19A Yuquan Road, Beijing 100049, China; State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
⁴ Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
⁵ Burning Rock Biotech, Shanghai 201114, China.
⁶ Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
⁷ Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
⁸ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
⁹ Frontiers Science Center for Disease-related Molecular Network, Institutes for Systems Genetics, Key Lab of Transplant Engineering and Immunology, MOH, West China Hospital, Sichuan University, Chengdu 610041, China.
¹⁰ Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Shanghai Institute of Materia Medica-University of Ottawa Joint Research Center in Systems and Personalized Pharmacology, 555 Zuchongzhi Road, Shanghai 201203, China.
¹¹ Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), The Collaborative Innovation Center for Brain Science, Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China.
¹² Department of Medicine, McDonnell Genome Institute, Siteman Cancer Center, Washington University, St. Louis, MI 63108, USA.
¹³ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NewYork, NY 10029, USA.
¹⁴ Office of Cancer Clinical Proteomics Research, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
¹⁵ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433, China. Electronic address: gaoqiang@fudan.edu.cn.
¹⁶ University of Chinese Academy of Sciences, Number 19A Yuquan Road, Beijing 100049, China; State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: dgao@sibcb.ac.cn.
¹⁷ Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, Number 19A Yuquan Road, Beijing 100049, China; Shanghai Institute of Materia Medica-University of Ottawa Joint Research Center in Systems and Personalized Pharmacology, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: zhouhu@simm.ac.cn.
¹⁸ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: fan.jia@zs-hospital.sh.cn.

PMID: 34971568
DOI: 10.1016/j.ccell.2021.12.006

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.

Keywords: FGFR2 fusion; intrahepatic cholangiocarcinoma; molecular subgroups; oncogenic drivers; prognostic biomarkers; proteogenomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bile Duct Neoplasms / genetics
Bile Duct Neoplasms / pathology*
Bile Ducts, Intrahepatic / pathology*
Cholangiocarcinoma / genetics
Cholangiocarcinoma / pathology*
Humans
Liver / pathology*
Mutation / genetics
Prognosis
Proteogenomics* / methods
Proteomics
Tumor Microenvironment / immunology