2. Academic Validation
  3. A compendium of Amplification-Related Gain Of Sensitivity genes in human cancer

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

  • Nat Commun. 2025 Jan 27;16(1):1077. doi: 10.1038/s41467-025-56301-2.
Veronica Rendo # 1 2 3 4 5,  Michael Schubert # 6 7 8 9,  Nicholas Khuu 10 11 12,  Maria F Suarez Peredo Rodriguez 13,  Declan Whyte 13,  Xiao Ling 13,  Anouk van den Brink 13,  Kaimeng Huang 12 14,  Michelle Swift 14,  Yizhou He 12 14,  Johanna Zerbib 15,  Ross Smith 16,  Jonne Raaijmakers 17,  Pratiti Bandopadhayay 18 12 19,  Lillian M Guenther 20,  Justin H Hwang 21,  Amanda Iniguez 22,  Susan Moody 10 18 12,  Ji-Heui Seo 10,  Elizabeth H Stover 10 18 12,  Levi Garraway 10 12,  William C Hahn 10 18 12,  Kimberly Stegmaier 18 12 19,  René H Medema 17,  Dipanjan Chowdhury 12 14,  Maria Colomé-Tatché 23 24,  Uri Ben-David 25,  Rameen Beroukhim 26 27 28 29,  Floris Foijer 30
Affiliations

Affiliations

  • 1 Department of Medical Oncology and Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. veronica.rendo@igp.uu.se.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. veronica.rendo@igp.uu.se.
  • 3 Harvard Medical School, Boston, MA, USA. veronica.rendo@igp.uu.se.
  • 4 Broad Institute of Harvard and MIT, Cambridge, MA, USA. veronica.rendo@igp.uu.se.
  • 5 Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. veronica.rendo@igp.uu.se.
  • 6 Oncode Institute, Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, Netherlands. m.schubert@nki.nl.
  • 7 European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, Netherlands. m.schubert@nki.nl.
  • 8 Institute of Computational Biology, Helmholtz Munich, Neuherberg, Germany. m.schubert@nki.nl.
  • 9 Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. m.schubert@nki.nl.
  • 10 Department of Medical Oncology and Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 11 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 12 Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 13 European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, Netherlands.
  • 14 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 15 Department of Human Molecular Genetics & Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 16 Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
  • 17 Oncode Institute, Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 18 Harvard Medical School, Boston, MA, USA.
  • 19 Department of Pediatrics, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 20 St. Jude Children's Research Hospital, Department of Oncology, Memphis, TN, USA.
  • 21 Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, USA.
  • 22 Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • 23 Institute of Computational Biology, Helmholtz Munich, Neuherberg, Germany.
  • 24 Biomedical Center (BMC), Physiological Chemistry, Ludwig Maximilians University, Munich, Germany.
  • 25 Department of Human Molecular Genetics & Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. ubendavid@tauex.tau.ac.il.
  • 26 Department of Medical Oncology and Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. rameen_beroukhim@dfci.harvard.edu.
  • 27 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. rameen_beroukhim@dfci.harvard.edu.
  • 28 Harvard Medical School, Boston, MA, USA. rameen_beroukhim@dfci.harvard.edu.
  • 29 Broad Institute of Harvard and MIT, Cambridge, MA, USA. rameen_beroukhim@dfci.harvard.edu.
  • 30 European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, Netherlands. f.foijer@umcg.nl.
  • # Contributed equally.
PMID: 39870664 DOI: 10.1038/s41467-025-56301-2
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.

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