Veronica Rendo, Michael Schubert, Nicholas Khuu, Maria F. Suarez Peredo Rodriguez, Declan Whyte, Xiao Ling, Anouk van den Brink, Kaimeng Huang, Michelle Swift, Yizhou He, Johanna Zerbib, Ross Smith, Jonne Raaijmakers, Pratiti Bandopadhayay, Lillian M. Guenther, Justin H. Hwang, Amanda Iniguez, Susan Moody, Ji-Heui Seo, Elizabeth H. Stover, Levi Garraway, William C. Hahn, Kimberly Stegmaier, René H. Medema, Dipanjan Chowdhury, Maria Colomé-Tatché, Uri Ben-David, Rameen Beroukhim, Floris Foijer
{"title":"人类癌症中敏感基因扩增相关增益简编","authors":"Veronica Rendo, Michael Schubert, Nicholas Khuu, Maria F. Suarez Peredo Rodriguez, Declan Whyte, Xiao Ling, Anouk van den Brink, Kaimeng Huang, Michelle Swift, Yizhou He, Johanna Zerbib, Ross Smith, Jonne Raaijmakers, Pratiti Bandopadhayay, Lillian M. Guenther, Justin H. Hwang, Amanda Iniguez, Susan Moody, Ji-Heui Seo, Elizabeth H. Stover, Levi Garraway, William C. Hahn, Kimberly Stegmaier, René H. Medema, Dipanjan Chowdhury, Maria Colomé-Tatché, Uri Ben-David, Rameen Beroukhim, Floris Foijer","doi":"10.1038/s41467-025-56301-2","DOIUrl":null,"url":null,"abstract":"<p>While the effect of amplification-induced oncogene expression in cancer is known, the impact of copy-number gains on “bystander” genes is less understood. We create a comprehensive map of dosage compensation in cancer by integrating expression and copy number profiles from over 8000 tumors in The Cancer Genome Atlas and cell lines from the Cancer Cell Line Encyclopedia. Additionally, we analyze 17 cancer open reading frame screens to identify genes toxic to cancer cells when overexpressed. Combining these approaches, we propose a class of ‘Amplification-Related Gain Of Sensitivity’ (ARGOS) genes located in commonly amplified regions, yet expressed at lower levels than expected by their copy number, and toxic when overexpressed. We validate RBM14 as an ARGOS gene in lung and breast cancer cells, and suggest a toxicity mechanism involving altered DNA damage response and STING signaling. We additionally observe increased patient survival in a radiation-treated cancer cohort with RBM14 amplification.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"119 1","pages":""},"PeriodicalIF":15.7000,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A compendium of Amplification-Related Gain Of Sensitivity genes in human cancer\",\"authors\":\"Veronica Rendo, Michael Schubert, Nicholas Khuu, Maria F. Suarez Peredo Rodriguez, Declan Whyte, Xiao Ling, Anouk van den Brink, Kaimeng Huang, Michelle Swift, Yizhou He, Johanna Zerbib, Ross Smith, Jonne Raaijmakers, Pratiti Bandopadhayay, Lillian M. Guenther, Justin H. Hwang, Amanda Iniguez, Susan Moody, Ji-Heui Seo, Elizabeth H. Stover, Levi Garraway, William C. Hahn, Kimberly Stegmaier, René H. Medema, Dipanjan Chowdhury, Maria Colomé-Tatché, Uri Ben-David, Rameen Beroukhim, Floris Foijer\",\"doi\":\"10.1038/s41467-025-56301-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>While the effect of amplification-induced oncogene expression in cancer is known, the impact of copy-number gains on “bystander” genes is less understood. We create a comprehensive map of dosage compensation in cancer by integrating expression and copy number profiles from over 8000 tumors in The Cancer Genome Atlas and cell lines from the Cancer Cell Line Encyclopedia. Additionally, we analyze 17 cancer open reading frame screens to identify genes toxic to cancer cells when overexpressed. Combining these approaches, we propose a class of ‘Amplification-Related Gain Of Sensitivity’ (ARGOS) genes located in commonly amplified regions, yet expressed at lower levels than expected by their copy number, and toxic when overexpressed. We validate RBM14 as an ARGOS gene in lung and breast cancer cells, and suggest a toxicity mechanism involving altered DNA damage response and STING signaling. We additionally observe increased patient survival in a radiation-treated cancer cohort with RBM14 amplification.</p>\",\"PeriodicalId\":19066,\"journal\":{\"name\":\"Nature Communications\",\"volume\":\"119 1\",\"pages\":\"\"},\"PeriodicalIF\":15.7000,\"publicationDate\":\"2025-01-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature Communications\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://doi.org/10.1038/s41467-025-56301-2\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Communications","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41467-025-56301-2","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
A compendium of Amplification-Related Gain Of Sensitivity genes in human cancer
While the effect of amplification-induced oncogene expression in cancer is known, the impact of copy-number gains on “bystander” genes is less understood. We create a comprehensive map of dosage compensation in cancer by integrating expression and copy number profiles from over 8000 tumors in The Cancer Genome Atlas and cell lines from the Cancer Cell Line Encyclopedia. Additionally, we analyze 17 cancer open reading frame screens to identify genes toxic to cancer cells when overexpressed. Combining these approaches, we propose a class of ‘Amplification-Related Gain Of Sensitivity’ (ARGOS) genes located in commonly amplified regions, yet expressed at lower levels than expected by their copy number, and toxic when overexpressed. We validate RBM14 as an ARGOS gene in lung and breast cancer cells, and suggest a toxicity mechanism involving altered DNA damage response and STING signaling. We additionally observe increased patient survival in a radiation-treated cancer cohort with RBM14 amplification.
期刊介绍：
Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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