Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
Nat Commun. 2022 May 4;13(1):2436. doi: 10.1038/s41467-022-29960-8.
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.
肝细胞癌 (HCC) 的蛋白质基因组分析主要集中在早期、HBV 相关的 HCC 上。在这里，我们对不同临床分期和病因的 HCC 进行了综合蛋白质基因组分析。与细胞周期、转录和翻译控制、信号转导以及代谢相关的途径在基因组、转录组、蛋白质组和磷酸化蛋白质组水平上失调和差异调节。我们描述了候选拷贝数驱动的参与上皮-间充质转化、Wnt-β-catenin、AKT/mTOR 和 Notch 途径、细胞周期和 DNA 损伤调节的驱动基因。可靶向的极光激酶 A 和细胞周期蛋白依赖性激酶被上调。CTNNB1 和 TP53 突变分别与肌动蛋白丝组织和脂质代谢相关的蛋白质磷酸化改变有关。综合蛋白质基因组聚类表明，HCC 构成了具有不同生物学过程、代谢重编程和激酶激活调节的异质亚组。我们的研究提供了 HCC 蛋白质组和磷酸蛋白质组图谱的全面概述，揭示了 (磷酸化) 蛋白质组中改变的主要途径。
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