AbstractIn 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.

摘要在癌症研究中，RAS生物学仅关注少数几种肿瘤类型。虽然长期以来人们一直怀疑RAS基因是多种癌症类型的常见贡献者，但需要强有力的证据来确定其关键的致癌意义。我们提出了一项使用DepMap全基因组CRISPR筛选数据的数据挖掘研究，该研究提供了大量证据来支持RAS基因突变的突出普遍致癌作用和组织特异性允许性。

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.

CRISPR效应评分的差异分析将K或N-RAS基因鉴定为跨越多种组织类型的（K，N，组合）RAS突变体与野生型细胞系对比中差异最大的基因。KRAS与NRAS作为组织类型子集中最高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参与组织类型的想法。

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..

据我们所知，这是基因依赖性数据揭示的RAS突变的显着普遍致癌作用的首次报道，该数据超出了目前对RAS基因及其众所周知的相关组织类型的致癌作用的理解。我们的发现强烈支持RAS突变作为传统公认的癌症类型之外的主要致癌驱动因素，并提供了对其组织特异性允许性的见解。。

IntroductionThe RAS genes (KRAS, NRAS, HRAS) hold significant historical importance as they were the first human oncogenes discovered in the field of cancer research. Moreover, they stand out as the most frequently mutated oncogenes in human cancers1,2,3,4. Notably, KRAS exhibits the highest frequency of mutations in Pancreatic Adenocarcinoma (PAAD), followed by Colon Adenocarcinoma (COAD) and Lung Adenocarcinoma (LUAD), which are also tumor types that garner considerable attention from the cancer research community1,4.However, it is crucial to recognize that RAS gene mutations occur in numerous other cancer types and are believed to play a pivotal role in the oncogenesis of approximately 20% of human cancers1,2,4.

引言RAS基因（KRAS，NRAS，HRAS）具有重要的历史意义，因为它们是癌症研究领域发现的第一个人类致癌基因。此外，它们是人类癌症中突变频率最高的癌基因1,2,3,4。值得注意的是，KRAS在胰腺癌（PAAD）中表现出最高的突变频率，其次是结肠腺癌（COAD）和肺腺癌（LUAD），这也是癌症研究界相当关注的肿瘤类型1,4。然而，认识到RAS基因突变发生在许多其他癌症类型中是至关重要的，并且被认为在大约20%的人类癌症的肿瘤发生中起关键作用1,2,4。

This suggests that RAS gene mutations may have a more extensive impact as oncogenic drivers than our current research focus suggests. Despite our ongoing efforts to advance our understanding of RAS biology, with a better understanding of RAS-engaged cancer types2,5,6, computational studies have also revealed that RAS genes possess potential oncogenic driver properties in various tumor or tissue types7,8,9.Over the past few years, the Cancer Dependency Map (DepMap) database has gained significant popularity as a valuable resource for data mining in cancer research fields10,11,12,13.

这表明RAS基因突变作为致癌驱动因素的影响可能比我们目前的研究重点所表明的更为广泛。尽管我们正在努力提高对RAS生物学的理解，但随着对RAS参与的癌症类型的更好理解2,5,6，计算研究还表明，RAS基因在各种肿瘤或组织类型中具有潜在的致癌驱动特性7,8,9。在过去的几年中，癌症依赖图（DepMap）数据库作为癌症研究领域数据挖掘的宝贵资源获得了极大的普及10,11,12,13。

Hosted primarily by the BROAD Institute and collaboratively supported by the Sanger Institute, the DepMap database serves as a comprehensive repository of genome-wide high-throughput genetic knockout screening data. It offers systematic means to assess genetic dependencies for genes of interest.The DepMap database incorporates diverse genomic data collections, including gene expression and mutation data.

DepMap数据库主要由BROAD Institute托管，并由Sanger Institute合作支持，是全基因组高通量基因敲除筛选数据的综合存储库。它提供了系统的方法来评估感兴趣基因的遗传依赖性。DepMap数据库包含多种基因组数据收集，包括基因表达和突变数据。

It houses genome-wide CRISPR screening data for approximately 1000 Cancer Cell.

它包含了大约1000个癌细胞的全基因组CRISPR筛选数据。

Data availability

数据可用性

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

在当前研究期间生成和/或分析的数据集可根据合理要求从通讯作者处获得。

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Download referencesAcknowledgementsThe authors would like to thank Jigui Shan for maintaining R environment and packages in servers. The authors also thank Frantz Jean-Francois, Peter Johnson, and Anna Maciag for helpful discussions about Ras biology and for their helpful suggestions after reading the manuscript.

下载参考文献致谢作者要感谢Jigui Shan在服务器中维护R环境和软件包。作者还感谢Frantz-Jean-Francois，Peter Johnson和Anna Maciag在阅读手稿后对Ras生物学的有益讨论以及他们的有益建议。

We would like to thank the editor and referees for helpful comments that led to improvements in this paper.FundingOpen access funding provided by the National Institutes of HealthAuthor informationAuthors and AffiliationsNCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USAMing Yi, Daniel Soppet, Frank McCormick & Dwight V.

我们要感谢编辑和裁判的有益评论，这些评论导致了本文的改进。基金开放获取资金由美国国立卫生研究院作者信息作者和附属机构NCI RAS倡议，癌症研究技术计划，弗雷德里克国家癌症研究实验室，弗雷德里克，医学博士，易国明，丹尼尔·索佩特，弗兰克·麦考密克和德怀特V。

NissleyUCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USAFrank McCormickAuthorsMing YiView author publicationsYou can also search for this author in.

NissleyUCSF Helen Diller家庭综合癌症中心，美国加利福尼亚州旧金山Frank McCormickAuthorsMing YiView作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarDaniel SoppetView author publicationsYou can also search for this author in

PubMed Google ScholarDaniel SoppetView作者出版物您也可以在

PubMed Google ScholarFrank McCormickView author publicationsYou can also search for this author in

PubMed Google ScholarFrank McCormickView作者出版物您也可以在

PubMed Google ScholarDwight V. NissleyView author publicationsYou can also search for this author in

PubMed Google ScholarDwight V.NissleyView作者出版物您也可以在

PubMed Google ScholarContributionsM.Y. conceived the study and designed the project. M.Y. performed data curation and download. M.Y. performed the data analysis, wrote the original draft of the manuscript and revised the manuscript. D.S., F.M., and D.V.N. revised the manuscript, and provided insightful suggestions for further data analysis.

PubMed谷歌学术贡献。Y、 构思了这项研究并设计了这个项目。M、 Y.执行数据管理和下载。M、 Y.进行了数据分析，撰写了稿件的初稿并修改了稿件。D、 S.，F.M。和D.V.N.修订了手稿，并为进一步的数据分析提供了有见地的建议。

All authors read and approved the final manuscript.Corresponding authorCorrespondence to.

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Reprints and permissionsAbout this articleCite this articleYi, M., Soppet, D., McCormick, F. et al. The prominent pervasive oncogenic role and tissue specific permissiveness of RAS gene mutations.

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Sci Rep 14, 25452 (2024). https://doi.org/10.1038/s41598-024-76591-8Download citationReceived: 03 June 2024Accepted: 15 October 2024Published: 26 October 2024DOI: https://doi.org/10.1038/s41598-024-76591-8Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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