Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma
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 wit...
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| Published in: | Cancer cell Vol. 40; no. 1; p. 70 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
10.01.2022
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| Subjects: | |
| ISSN: | 1878-3686, 1878-3686 |
| Online Access: | Get more information |
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| 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. |
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| AbstractList | 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. 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.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. |
| Author | Zhang, Xiaoming Zhou, Jian Lin, Youpei Rodriguez, Henry Lu, Dayun Shi, Yongyong Figeys, Daniel Cai, Shangli Rao, Dongning Gao, Qiang Zou, Yunhao Ding, Li Song, Guohe Yi, Xinpei Dong, Liangqing Zhang, Zhou Wang, Xiaoying Fan, Jia Zhang, Bing Cui, Peng Zhang, Xu Gao, Daming Liu, Fen Wang, Shisheng Song, Nixue Qiu, Shuangjian Wu, Yingcheng Chen, Ran Zhou, Hu Zhu, Hongwen Zhang, Shu Wang, Pei |
| Author_xml | – sequence: 1 givenname: Liangqing surname: Dong fullname: Dong, Liangqing organization: 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 – sequence: 2 givenname: Dayun surname: Lu fullname: Lu, Dayun organization: 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 – sequence: 3 givenname: Ran surname: Chen fullname: Chen, Ran organization: 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 – sequence: 4 givenname: Youpei surname: Lin fullname: Lin, Youpei organization: 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 – sequence: 5 givenname: Hongwen surname: Zhu fullname: Zhu, Hongwen organization: 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 – sequence: 6 givenname: Zhou surname: Zhang fullname: Zhang, Zhou organization: Burning Rock Biotech, Shanghai 201114, China – sequence: 7 givenname: Shangli surname: Cai fullname: Cai, Shangli organization: Burning Rock Biotech, Shanghai 201114, China – sequence: 8 givenname: Peng surname: Cui fullname: Cui, Peng organization: Burning Rock Biotech, Shanghai 201114, China – sequence: 9 givenname: Guohe surname: Song fullname: Song, Guohe organization: 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 – sequence: 10 givenname: Dongning surname: Rao fullname: Rao, Dongning organization: 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 – sequence: 11 givenname: Xinpei surname: Yi fullname: Yi, Xinpei organization: Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA – sequence: 12 givenname: Yingcheng surname: Wu fullname: Wu, Yingcheng organization: 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 – sequence: 13 givenname: Nixue surname: Song fullname: Song, Nixue organization: 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 – sequence: 14 givenname: Fen surname: Liu fullname: Liu, Fen organization: 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 – sequence: 15 givenname: Yunhao surname: Zou fullname: Zou, Yunhao organization: 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 – sequence: 16 givenname: Shu surname: Zhang fullname: Zhang, Shu organization: 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 – sequence: 17 givenname: Xiaoming surname: Zhang fullname: Zhang, Xiaoming organization: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China – sequence: 18 givenname: Xiaoying surname: Wang fullname: Wang, Xiaoying organization: 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 – sequence: 19 givenname: Shuangjian surname: Qiu fullname: Qiu, Shuangjian organization: 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 – sequence: 20 givenname: Jian surname: Zhou fullname: Zhou, Jian organization: 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 – sequence: 21 givenname: Shisheng surname: Wang fullname: Wang, Shisheng organization: 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 – sequence: 22 givenname: Xu surname: Zhang fullname: Zhang, Xu organization: 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 – sequence: 23 givenname: Yongyong surname: Shi fullname: Shi, Yongyong organization: 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 – sequence: 24 givenname: Daniel surname: Figeys fullname: Figeys, Daniel organization: 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 – sequence: 25 givenname: Li surname: Ding fullname: Ding, Li organization: Department of Medicine, McDonnell Genome Institute, Siteman Cancer Center, Washington University, St. Louis, MI 63108, USA – sequence: 26 givenname: Pei surname: Wang fullname: Wang, Pei organization: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NewYork, NY 10029, USA – sequence: 27 givenname: Bing surname: Zhang fullname: Zhang, Bing organization: Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA – sequence: 28 givenname: Henry surname: Rodriguez fullname: Rodriguez, Henry organization: Office of Cancer Clinical Proteomics Research, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 29 givenname: Qiang surname: Gao fullname: Gao, Qiang email: gaoqiang@fudan.edu.cn organization: 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 – sequence: 30 givenname: Daming surname: Gao fullname: Gao, Daming email: dgao@sibcb.ac.cn organization: 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 – sequence: 31 givenname: Hu surname: Zhou fullname: Zhou, Hu email: zhouhu@simm.ac.cn organization: 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 – sequence: 32 givenname: Jia surname: Fan fullname: Fan, Jia email: fan.jia@zs-hospital.sh.cn organization: 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 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/34971568$$D View this record in MEDLINE/PubMed |
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| DOI | 10.1016/j.ccell.2021.12.006 |
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| Keywords | prognostic biomarkers molecular subgroups oncogenic drivers proteogenomics intrahepatic cholangiocarcinoma FGFR2 fusion |
| Language | English |
| License | Copyright © 2021 Elsevier Inc. All rights reserved. |
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| PublicationTitle | Cancer cell |
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| PublicationYear | 2022 |
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| Snippet | We performed proteogenomic characterization of intrahepatic cholangiocarcinoma (iCCA) using paired tumor and adjacent liver tissues from 262 patients.... |
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| SubjectTerms | 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 |
| Title | Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma |
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