The year 2021 marks the 20th anniversary of the first publications reporting the discovery of the gene silencing mechanism, RNA interference (RNAi) in mammalian cells. Along with the many studies that delineated the proteins and substrates that form the RNAi pathway, this finding changed our understanding of the posttranscriptional regulation of mammalian gene expression. Furthermore, the development of methods that exploited the RNAi pathway began the technological revolution that eventually enabled the interrogation of mammalian gene function—from a single gene to the whole genome—in only a few days. The needs of the cancer research community have driven much of this progress. In this perspective, we highlight milestones in the development and application of RNAi‐based methods to study carcinogenesis. We discuss how RNAi‐based functional genetic analysis of exemplar tumor suppressors and oncogenes furthered our understanding of cancer initiation and progression and explore how such studies formed the basis of genome‐wide scale efforts to identify cancer or cancer‐type specific vulnerabilities, including studies conducted in vivo. Furthermore, we examine how RNAi technologies have revealed new cancer‐relevant molecular targets and the implications for cancer of the first RNAi‐based drugs. Finally, we discuss the future of functional genetic analysis, highlighting the increasing availability of complementary approaches to analyze cancer gene function.

中文翻译：

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癌症生物学功能基因组学：从小 RNA 到大梦想

2021 年是第一篇报道哺乳动物细胞中基因沉默机制 RNA 干扰 (RNAi) 发现的出版物发表 20 周年。随着许多研究描述了形成 RNAi 通路的蛋白质和底物，这一发现改变了我们对哺乳动物基因表达转录后调控的理解。此外，利用 RNAi 途径的方法的开发开始了技术革命，最终能够在短短几天内对哺乳动物基因功能进行研究——从单个基因到整个基因组。癌症研究界的需求推动了这一进展。从这个角度来看，我们强调了基于 RNAi 的方法的开发和应用研究致癌作用的里程碑。我们讨论了基于 RNAi 的示例性肿瘤抑制基因和癌基因的功能遗传分析如何进一步加深我们对癌症发生和进展的理解，并探讨这些研究如何成为全基因组范围内识别癌症或癌症类型特定脆弱性的基础，包括开展的研究体内。此外，我们研究了 RNAi 技术如何揭示新的癌症相关分子靶点以及第一个基于 RNAi 的药物对癌症的影响。最后，我们讨论了功能遗传分析的未来，强调了分析癌症基因功能的补充方法的日益普及。