A compendium of Amplification-Related Gain Of Sensitivity genes in human cancer

Veronica Rendo (), Michael Schubert (), Nicholas Khuu, Maria F. Suarez Peredo Rodriguez, Declan Whyte, Xiao Ling, Anouk 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 () and Floris Foijer ()
Additional contact information
Veronica Rendo: Dana-Farber Cancer Institute
Michael Schubert: The Netherlands Cancer Institute
Nicholas Khuu: Dana-Farber Cancer Institute
Maria F. Suarez Peredo Rodriguez: University Medical Center Groningen
Declan Whyte: University Medical Center Groningen
Xiao Ling: University Medical Center Groningen
Anouk Brink: University Medical Center Groningen
Kaimeng Huang: Broad Institute of Harvard and MIT
Michelle Swift: Dana-Farber Cancer Institute
Yizhou He: Broad Institute of Harvard and MIT
Johanna Zerbib: Tel Aviv University
Ross Smith: Uppsala University
Jonne Raaijmakers: The Netherlands Cancer Institute
Pratiti Bandopadhayay: Harvard Medical School
Lillian M. Guenther: Department of Oncology
Justin H. Hwang: University of Minnesota
Amanda Iniguez: Perelman School of Medicine at the University of Pennsylvania
Susan Moody: Dana-Farber Cancer Institute
Ji-Heui Seo: Dana-Farber Cancer Institute
Elizabeth H. Stover: Dana-Farber Cancer Institute
Levi Garraway: Dana-Farber Cancer Institute
William C. Hahn: Dana-Farber Cancer Institute
Kimberly Stegmaier: Harvard Medical School
René H. Medema: The Netherlands Cancer Institute
Dipanjan Chowdhury: Broad Institute of Harvard and MIT
Maria Colomé-Tatché: Helmholtz Munich
Uri Ben-David: Tel Aviv University
Rameen Beroukhim: Dana-Farber Cancer Institute
Floris Foijer: University Medical Center Groningen

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-56301-2

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