In-Depth Serum Proteomics Reveals the Trajectory of Hallmarks of Cancer in Hepatitis B Virus–Related Liver Diseases

• Published in: Molecular & cellular proteomics 2023-07, Vol.22 (7), p.100574-100574, Article 100574
• Main Authors: Xu, Meng, Xu, Kaikun, Yin, Shangqi, Chang, Cheng, Sun, Wei, Wang, Guibin, Zhang, Kai, Mu, Jinsong, Wu, Miantao, Xing, Baocai, Zhang, Xiaomei, Han, Jinyu, Zhao, Xiaohang, Wang, Yajie, Xu, Danke, Yu, Xiaobo
• Format: Article
• Language: English
• Subjects: antibody array; biomarker; Biomarkers; Biomarkers, Tumor; Carcinoma, Hepatocellular - pathology; drug target; Hepatitis B virus; Hepatitis B, Chronic - complications; Hepatitis B, Chronic - diagnosis; hepatocellular carcinoma; Humans; Liver Cirrhosis - complications; Liver Cirrhosis - diagnosis; Liver Neoplasms - pathology; mass spectrometry; Proteomics; ROC Curve
• ISSN: 1535-9476; 1535-9484
• DOI: 10.1016/j.mcpro.2023.100574

Hepatocellular carcinoma (HCC) is a prevalent cancer in China, with chronic hepatitis B (CHB) and liver cirrhosis (LC) being high-risk factors for developing HCC. Here, we determined the serum proteomes (762 proteins) of 125 healthy controls and Hepatitis B virus–infected CHB, LC, and HCC patients and constructed the first cancerous trajectory of liver diseases. The results not only reveal that the majority of altered biological processes were involved in the hallmarks of cancer (inflammation, metastasis, metabolism, vasculature, and coagulation) but also identify potential therapeutic targets in cancerous pathways (i.e., IL17 signaling pathway). Notably, the biomarker panels for detecting HCC in CHB and LC high-risk populations were further developed using machine learning in two cohorts comprised of 200 samples (discovery cohort = 125 and validation cohort = 75). The protein signatures significantly improved the area under the receiver operating characteristic curve of HCC (CHB discovery and validation cohort = 0.953 and 0.891, respectively; LC discovery and validation cohort = 0.966 and 0.818, respectively) compared to using the traditional biomarker, alpha-fetoprotein, alone. Finally, selected biomarkers were validated with parallel reaction monitoring mass spectrometry in an additional cohort (n = 120). Altogether, our results provide fundamental insights into the continuous changes of cancer biology processes in liver diseases and identify candidate protein targets for early detection and intervention. [Display omitted] •Determined the serum proteomes of liver diseases using DIA-MS and antibody arrays.•Constructed the first cancerous trajectory of liver diseases.•Identified biomarker panels for LC and HCC patients that are superior to AFP. We determined the serum proteomes of 125 healthy controls and Hepatitis B virus-infected CHB, LC, and HCC patients using DIA-MS and customized antibody microarrays, and built the first cancerous trajectory of liver diseases. The results revealed the altered biological processes involved in the hallmarks of cancer and identified potential therapeutic targets in cancerous pathways. Notably, the biomarker panels for detecting HCC in CHB and LC high-risk populations were further developed using machine learning with significantly improved performance compared to AFP.