Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA.
Josep Carreras Leukaemia Research Institute (IJC), Badalona 08916, Spain; Barcelona Supercomputing Center (BSC), Barcelona 08034, Spain.
Cell. 2023 Aug 31;186(18):3921-3944.e25. doi: 10.1016/j.cell.2023.07.014. Epub 2023 Aug 14.
Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our multi-omics pan-cancer analysis uncovers insights into the impacts of cancer drivers by identifying their significant cis-effects and distal trans-effects quantified at the RNA, protein, and phosphoprotein levels. Salient observations include the association of point mutations and copy-number alterations with the rewiring of protein interaction networks, and notably, most cancer genes converge toward similar molecular states denoted by sequence-based kinase activity profiles. A correlation between predicted neoantigen burden and measured T cell infiltration suggests potential vulnerabilities for immunotherapies. Patterns of cancer hallmarks vary by polygenic protein abundance ranging from uniform to heterogeneous. Overall, our work demonstrates the value of comprehensive proteogenomics in understanding the functional states of oncogenic drivers and their links to cancer development, surpassing the limitations of studying individual cancer types.
癌症驱动事件是指导致肿瘤发生的关键遗传异常；然而，其确切的分子机制仍了解不足。在这里，我们的多组学泛癌分析通过识别在 RNA、蛋白质和磷酸化蛋白质水平上定量的显著顺式效应和远端转录效应，揭示了癌症驱动因素的影响。突出的观察结果包括点突变和拷贝数改变与蛋白质相互作用网络重布线的关联，值得注意的是，大多数癌症基因都趋向于由基于序列的激酶活性谱表示的相似分子状态。预测的新抗原负担与测量的 T 细胞浸润之间的相关性表明了免疫疗法的潜在弱点。癌症特征的模式因多基因蛋白丰度而异，从均匀到异质。总的来说，我们的工作表明综合蛋白质基因组学在理解致癌驱动因素的功能状态及其与癌症发展的联系方面具有价值，超越了研究个别癌症类型的局限性。
