NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
Sci Rep. 2024 Oct 26;14(1):25452. doi: 10.1038/s41598-024-76591-8.
In cancer research, RAS biology has been focused on only a handful of tumor types. While RAS genes have long been suspected as common contributors to a wide spectrum of cancer types, robust evidence is required to firmly establish their critical oncogenic significance. We present a data mining study using DepMap genome-wide CRISPR screening data, which provide substantial evidence to support the prominent pervasive oncogenic role and tissue-specific permissiveness of RAS gene mutations. Differential analysis of CRISPR effect scores identifies K- or N-RAS genes as the most differential gene in contrasts of (K-, N-, combined) RAS mutant versus wild-type cell lines across multiple tissue types. The distinguished tissue-specific pattern of KRAS vs. NRAS as top differential genes in subsets of tissue types and evidence from genome data supported the idea of KRAS- and NRAS-engaged tissue types. To our knowledge, this is the first report of prominent pervasive oncogenic role of RAS mutations revealed by gene dependency data that is beyond the current understanding of the oncogenic role of RAS genes and their well-known involved tissue types. Our findings strongly support RAS mutations as primary oncogenic drivers beyond traditionally recognized cancer types and offer insights into their tissue-specific permissiveness.
在癌症研究中，RAS 生物学主要集中在少数几种肿瘤类型上。虽然 RAS 基因长期以来一直被怀疑是广泛的癌症类型的常见贡献者，但需要确凿的证据来确定它们的关键致癌意义。我们提出了一项数据挖掘研究，使用了 DepMap 全基因组 CRISPR 筛选数据，这些数据提供了大量证据，支持 RAS 基因突变在广泛的肿瘤类型中具有突出的普遍致癌作用和组织特异性许可。CRISPR 效应评分的差异分析确定 K-或 N-RAS 基因为在多个组织类型中（K-、N-、联合）RAS 突变体与野生型细胞系的对比中最具差异的基因。KRAS 和 NRAS 作为组织类型子集的顶级差异基因的独特组织特异性模式以及来自基因组数据的证据支持了 KRAS 和 NRAS 参与的组织类型的观点。据我们所知，这是第一个通过基因依赖性数据揭示 RAS 突变具有突出的普遍致癌作用的报告，超出了目前对 RAS 基因致癌作用及其众所周知的相关组织类型的理解。我们的研究结果强烈支持 RAS 突变作为主要的致癌驱动因素，超越了传统上公认的癌症类型，并为它们的组织特异性许可提供了深入的了解。
