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 年是首次发表报告发现哺乳动物细胞中的基因沉默机制、RNA 干扰 (RNAi) 的出版物 20 周年。连同许多描述形成 RNAi 途径的蛋白质和底物的研究一起，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 途径的方法的开发引发了技术革命，最终能够在短短几天内研究哺乳动物的基因功能——从单个基因到整个基因组。癌症研究界的需求在很大程度上推动了这一进展。从这个角度来看，我们重点介绍基于 RNAi 的癌症发生研究方法的开发和应用的里程碑。我们讨论基于 RNAi 的示例肿瘤抑制基因和癌基因的功能遗传分析如何加深我们对癌症发生和进展的理解，并探讨这些研究如何构成全基因组范围努力的基础，以识别癌症或癌症类型的特定脆弱性，包括进行的研究体内。此外，我们还研究了 RNAi 技术如何揭示新的癌症相关分子靶标以及第一个基于 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可用性不断增加。