Integrated Proteogenomic Characterization of HBV-Related Hepatocellular Carcinoma

Qiang Gao; Hongwen Zhu; Liangqing Dong; Weiwei Shi; Ran Chen; Zhijian Song; Chen Huang; Junqiang Li; Xiaowei Dong; Yanting Zhou; Qian Liu; Lijie Ma; Xiaoying Wang; Jian Zhou; Yansheng Liu; Emily Boja; Ana I Robles; Weiping Ma; Pei Wang; Yize Li; Li Ding; Bo Wen; Bing Zhang; Henry Rodriguez; Daming Gao; Hu Zhou; Jia Fan

doi:10.1016/j.cell.2019.08.052

Integrated Proteogenomic Characterization of HBV-Related Hepatocellular Carcinoma

Cell. 2019 Oct 3;179(2):561-577.e22. doi: 10.1016/j.cell.2019.08.052.

Authors

Qiang Gao¹, Hongwen Zhu², Liangqing Dong¹, Weiwei Shi³, Ran Chen⁴, Zhijian Song³, Chen Huang⁵, Junqiang Li³, Xiaowei Dong³, Yanting Zhou², Qian Liu⁶, Lijie Ma¹, Xiaoying Wang¹, Jian Zhou⁷, Yansheng Liu⁸, Emily Boja⁹, Ana I Robles⁹, Weiping Ma¹⁰, Pei Wang¹⁰, Yize Li¹¹, Li Ding¹¹, Bo Wen⁵, Bing Zhang⁵, Henry Rodriguez⁹, Daming Gao¹², Hu Zhou¹³, Jia Fan¹⁴

Affiliations

¹ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, 180 Fenglin Road, 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.
³ OrigiMed, Shanghai 201114, China.
⁴ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, 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.
⁵ Department of Molecular and Human Genetics, Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston,TX 77030, USA.
⁶ 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.
⁷ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, 180 Fenglin Road, Shanghai 200032, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
⁸ Department of Pharmacology, Cancer Biology Institute, Yale University School of Medicine, West Haven, CT 06516, USA.
⁹ Office of Cancer Clinical Proteomics Research, Center for Strategic Scientific Initiatives, National Cancer Institutel, NIH, Bethesda, MD 20892, USA.
¹⁰ Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹¹ Department of Medicine, McDonnell Genome Institute, Siteman Cancer Center, Washington University, St. Louis, MO 63108, USA.
¹² State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, 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. Electronic address: dgao@sibcb.ac.cn.
¹³ 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. Electronic address: zhouhu@simm.ac.cn.
¹⁴ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, 180 Fenglin Road, 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: 31585088
DOI: 10.1016/j.cell.2019.08.052

Abstract

We performed the first proteogenomic characterization of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) using paired tumor and adjacent liver tissues from 159 patients. Integrated proteogenomic analyses revealed consistency and discordance among multi-omics, activation status of key signaling pathways, and liver-specific metabolic reprogramming in HBV-related HCC. Proteomic profiling identified three subgroups associated with clinical and molecular attributes including patient survival, tumor thrombus, genetic profile, and the liver-specific proteome. These proteomic subgroups have distinct features in metabolic reprogramming, microenvironment dysregulation, cell proliferation, and potential therapeutics. Two prognostic biomarkers, PYCR2 and ADH1A, related to proteomic subgrouping and involved in HCC metabolic reprogramming, were identified. CTNNB1 and TP53 mutation-associated signaling and metabolic profiles were revealed, among which mutated CTNNB1-associated ALDOA phosphorylation was validated to promote glycolysis and cell proliferation. Our study provides a valuable resource that significantly expands the knowledge of HBV-related HCC and may eventually benefit clinical practice.

Keywords: AA signature; ALDOA; CTNNB1; hepaotcellular carcinoma; metabolism; neoantigen; prognosis; proteogenomics; proteomics.

Publication types

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

MeSH terms

Animals
Carcinoma, Hepatocellular / genetics*
Carcinoma, Hepatocellular / virology*
Cell Proliferation
Cohort Studies
Female
Fructose-Bisphosphate Aldolase / genetics*
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Hep G2 Cells
Hepatitis B virus*
Hepatitis B, Chronic / complications*
Humans
Liver Neoplasms / genetics*
Liver Neoplasms / virology*
Male
Mice
Mice, Inbred BALB C
Middle Aged
Proteogenomics / methods*
Tumor Microenvironment / genetics
beta Catenin / genetics*

Substances

CTNNB1 protein, human
beta Catenin
ALDOA protein, human
Fructose-Bisphosphate Aldolase