Liver cancer ranks the fourth leading cause of cancer-related death worldwide. Hepatocellular carcinoma (HCC) accounts for about 85%–90% of all primary liver malignancies, and the largest attributable causes are chronic infection by hepatitis B virus (HBV) and hepatitis C virus (HCV), along with alcohol abuse and metabolic syndrome.

Notably, HBV-related HCC accounts for about 85% of HCC cases in China, due to the high prevalence of HBV infection. The clinical practice and effective treatment to patients largely rely on high quality basic research with advanced technologies.

In an article published on October 3 in the journal Cell, experts report 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.

The combined application of next-generation sequencing and state-of-the-art mass spectrometry technologies and the subsequent integrated multi-omics analyses provide a unique opportunity to understand HBV-related HCC from a systematic level.

The data revealed a distinguishable mutation profile of HBV-related HCC cohort compared to HCV-related HCC cohort. One third of the patients seemed to be affected by aristolochic acid-associated genetic mutation and may be potentially benefitted from immunotherapy.

The 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 proteins related to metabolic reprogramming (PYCR2 and ADH1A) were identified. The multiple-omics analysis suggested that CTNNB1 mutation is associated with deregulated glycolysis metabolism in tumor tissues, such as phosphorylation of ALDOA.

The main resource for reporting proteogenomic study of HBV-related HCC not only provides a high-quality proteogenomic resource of HBV-related HCC complementary to TCGA, but also implicates promising prognostic and therapeutic significance and underlying regulatory mechanisms that may benefit clinical practice.

This work was done under the auspices of a Memorandum of Understanding between the Shanghai Institute of Materia Medica, Chinese Academy of Science, Fudan University, and the U.S. National Cancer Institute’s Office of Cancer Clinical Proteomics Research (Clinical Proteomic Tumor Analysis Consortium – CPTAC).
（web address：https://www.sciencedirect.com/science/article/pii/S0092867419310037）

Summary of the integrated proteogenomic analysis of HBV-related Hepatocellular Carcinoma (Image by ZHU Hongwen)

From Prof. Zhou Hu’s Group, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences.
Email: zhouhu@simm.ac.cn