Integrative proteogenomic characterization of hepatocellular carcinoma across etiologies and stages

Abstract

Proteogenomic analyses of hepatocellular carcinomas (HCC) have focused on early-stage, HBV-associated HCCs. Here we present an integrated proteogenomic analysis of HCCs across clinical stages and etiologies. Pathways related to cell cycle, transcriptional and translational control, signaling transduction, and metabolism are dysregulated and differentially regulated on the genomic, transcriptomic, proteomic and phosphoproteomic levels. We describe candidate copy number-driven driver genes involved in epithelial-to-mesenchymal transition, the Wnt-β-catenin, AKT/mTOR and Notch pathways, cell cycle and DNA damage regulation. The targetable aurora kinase A and CDKs are upregulated. CTNNB1 and TP53 mutations are associated with altered protein phosphorylation related to actin filament organization and lipid metabolism, respectively. Integrative proteogenomic clusters show that HCC constitutes heterogeneous subgroups with distinct regulation of biological processes, metabolic reprogramming and kinase activation. Our study provides a comprehensive overview of the proteomic and phophoproteomic landscapes of HCCs, revealing the major pathways altered in the (phospho)proteome.

Integrated proteogenomic characterization and immune response evaluation reveal an imbalanced hepatocellular carcinoma microenvironment induced by incomplete radiofrequency ablation

“…Interestingly, there were more translational regulation-related genes dysregulated at the mRNA level than at the protein level. One possible explanation is that increased transcription of genes acts as a compensatory mechanism for protein degradation [30]. Third, we identi ed PRTN3 as a frequently mutated driver gene in iRFA-triggered HCC progression and recurrence.…”

Comparison of single‑nucleus and single‑cell transcriptomes in hepatocellular carcinoma tissue

“…Results of the present study demonstrated that scRNA-seq identified a low number of hepatocytes, which differed to the results obtained from previous studies ( 25 , 26 ). This may be due to HCC exhibiting a large organizational heterogeneity ( 27 ). Certain HCC tissues contain a high number of HCC cells, while others contain an increased number of non-parenchymal cells, such as fibroblasts ( 27 , 28 ).…”

“…This may be due to HCC exhibiting a large organizational heterogeneity ( 27 ). Certain HCC tissues contain a high number of HCC cells, while others contain an increased number of non-parenchymal cells, such as fibroblasts ( 27 , 28 ). HCC develops from hepatitis B cirrhosis, when liver tissue contains a lot of fiber and the number of liver cells is reduced ( 29 ).…”

Hepatocellular carcinoma mutation landscape and its differences between Asians and Whites

“…Heterogeneity is manifested as interindividual heterogeneity and intratumoral heterogeneity, and the latter also manifests as temporal and spatial heterogeneity, which shed light on the individualized and precise treatment for HCC. Owing to the advance in genomics, proteomics, and transcriptomics, plenty of molecular pathogenesis, drivers, and molecular and immune classes of HCC have been identified and many novel agents either molecular targets or immune check-point inhibitors (ICIs) have been developed and marked with promising results ( 6 , 7 ). Nonetheless, data revealed that only 25% of tumors harbor one druggable target mainly due to tumor heterogeneity ( 4 , 8 ).…”

“…Nonetheless, data revealed that only 25% of tumors harbor one druggable target mainly due to tumor heterogeneity ( 4 , 8 ). In addition, off-target and treatment resistance are also dilemmas after marking ( 4 , 6 , 7 ). As a result, the understanding of oncogenic drivers and molecular classes has not yet ceased.…”