在诸如癌症依赖基因图谱等项目中，已经针对多样的癌症类型进行了大量的功能基因组筛选，以鉴定基因依赖性——失去功能会降低细胞存活能力或适应性的基因。最近，大规模筛选工作已经从RNA干扰转向CRISPR-Cas9，因为其效果和特异性更为优越。然而，许多有效的肿瘤学药物仅部分抑制其蛋白靶标，这使我们质疑是否使用RNA干扰的方式部分抑制基因会揭示CRISPR-Cas9完全敲除所遗漏的癌症易感性。在这里，我们比较了大约400个配对癌细胞系的CRISPR-Cas9和RNA干扰依赖性谱。我们发现CRISPR筛选可以准确识别出更多的基因依赖性，但是每个细胞系的大部分依赖性基因都属于包括1867个共生依赖基因在内的一组共享依赖基因（全集致命基因）。虽然这些基因中约30%的RNA干扰也是全集致命的，但约50%的基因在细胞系间具有选择性依赖模式，这表明它们仍然可能是癌症易感性基因。对于这种独特的RNA干扰选择性的准确性得到了与多组学数据、药物敏感性和其他预期互依赖性的关联支持。将全集致命敲除的RNA干扰数据纳入考虑，有助于发现更广泛的基因靶标范围，这是仅使用CRISPR数据无法检测出的。这有助于解释来自CRISPR和RNA干扰筛选的对比结果，并强调了部分基因抑制方法在构建癌症依赖性图谱中的重要性。（©2023年, BioMed Central股份有限公司，Springer Nature的一部分。）

Hundreds of functional genomic screens have been performed across a diverse set of cancer contexts, as part of efforts such as the Cancer Dependency Map, to identify gene dependencies-genes whose loss of function reduces cell viability or fitness. Recently, large-scale screening efforts have shifted from RNAi to CRISPR-Cas9, due to superior efficacy and specificity. However, many effective oncology drugs only partially inhibit their protein targets, leading us to question whether partial suppression of genes using RNAi could reveal cancer vulnerabilities that are missed by complete knockout using CRISPR-Cas9. Here, we compare CRISPR-Cas9 and RNAi dependency profiles of genes across approximately 400 matched cancer cell lines.We find that CRISPR screens accurately identify more gene dependencies per cell line, but the majority of each cell line's dependencies are part of a set of 1867 genes that are shared dependencies across the entire collection (pan-lethals). While RNAi knockdown of about 30% of these genes is also pan-lethal, approximately 50% have selective dependency patterns across cell lines, suggesting they could still be cancer vulnerabilities. The accuracy of the unique RNAi selectivity is supported by associations to multi-omics profiles, drug sensitivity, and other expected co-dependencies.Incorporating RNAi data for genes that are pan-lethal knockouts facilitates the discovery of a wider range of gene targets than could be detected using the CRISPR dataset alone. This can aid in the interpretation of contrasting results obtained from CRISPR and RNAi screens and reinforce the importance of partial gene suppression methods in building a cancer dependency map.© 2023. BioMed Central Ltd., part of Springer Nature.