Identification of Survival-Related Predictors in Hepatocellular Carcinoma Through Integrated Genomic, Transcriptomic, and Proteomic Analyses

Abstract

Patient survival time generally reflects the tumor progression and represents a key clinical parameter. In this study, using copy-number changes, gene mutations, mRNA expression, and reverse phase protein arrays data in hepatocellular carcinoma (HCC) samples with poor and better clinical outcome profiled by The Cancer Genome Atlas (TCGA), we performed comprehensive molecular characterization of prognosisassociated alterations. Among them, several copy number amplifications and deletions can discriminate HCC patients with poor prognosis from those with better prognosis. Mutated DNAH8 showed a worse prognosisspecific pattern and correlated with a reduced disease-free survival in HCC. By integrating RNA sequencing data, we found that HCC samples with poor prognosis are consistently associated with the up-regulation of cell cycle process, such as chromosome separation, DNA replication, cytokinesis, and etc. At the proteomic level, seven proteins were significantly enriched in samples with poor prognosis, including acetylated α-Tubulin, p62-LCK-ligand, ARID1A, MSH6, B-Raf, Cyclin B1, and PEA15. Acetylated α-Tubulin was frequently expressed in HCC tissues and acted as a promising prognostic factor for HCC. Collectively, these alterations lay a foundation for developing relevant therapeutic strategies and improve our knowledge of the pathogenesis of HCC. Funding Statement: The research was supported by grants from Shanghai Municipal Commission of Health and Family Planning, Key Developing Disciplines Program (No: 2015ZB0501), Shanghai Key disciplines program of Health and Family Planning (No: 2017ZZ02010), Shanghai Sailing Program (No: 17YF1405200), and National Natural Science Foundation of China (81701374). Declaration of Interests: The authors state: Nothing to report. Ethics Approval Statement: All human samples were obtained with informed consent, and protocols were approved by the ethical review committee of the World Health Organization Collaborating Center for Research in Human Production (authorized by the Shanghai Municipal Government).