Integrative analysis of layers of data in hepatocellular carcinoma reveals pathway dependencies

Abstract

BACKGROUND The broader use of high-throughput technologies has led to improved molecular characterization of hepatocellular carcinoma (HCC). AIM To comprehensively analyze and characterize all publicly available genomic, gene expression, methylation, miRNA and proteomic data in HCC, covering 85 studies and 3355 patient sample profiles, to identify the key dysregulated genes and pathways they affect. METHODS We collected and curated all well-annotated and publicly available high-throughput datasets from PubMed and Gene Expression Omnibus derived from human HCC tissue. Comprehensive pathway enrichment analysis was performed using pathDIP for each data type (genomic, gene expression, methylation, miRNA and proteomic), and the overlap of pathways was assessed to elucidate pathway dependencies in HCC. RESULTS We identified a total of 8733 abstracts retrieved by the search on PubMed on HCC for the different layers of data on human HCC samples, published until December 2016. The common key dysregulated pathways in HCC tissue across different layers of data included epidermal growth factor (EGFR) and β1-integrin pathways. Genes along these pathways were significantly and consistently dysregulated across the different types of high-throughput data and had prognostic value with respect to overall survival. Using CTD database, estradiol would best modulate and revert these genes appropriately. CONCLUSION By analyzing and integrating all available high-throughput genomic, transcriptomic, miRNA, methylation and proteomic data from human HCC tissue, we identified EGFR, β1-integrin and axon guidance as pathway dependencies in HCC. These are master regulators of key pathways in HCC, such as the mTOR, Ras/Raf/MAPK and p53 pathways. The genes implicated in these pathways had prognostic value in HCC, with Netrin and Slit3 being novel proteins of prognostic importance to HCC. Based on this integrative analysis, EGFR, and β1-integrin are master regulators that could serve as potential therapeutic targets in HCC.