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

Integrated Proteogenomic Characterization of HBV-Related Hepatocellular Carcinoma.

Author information

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.

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

PMID:
31585088
DOI:
10.1016/j.cell.2019.08.052
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