Nature Communications (Jan 2025)
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 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
Affiliations
- Veronica Rendo
- Department of Medical Oncology and Center for Neuro-Oncology, Dana-Farber Cancer Institute
- Michael Schubert
- Oncode Institute, Division of Cell Biology, The Netherlands Cancer Institute
- Nicholas Khuu
- Department of Medical Oncology and Center for Neuro-Oncology, Dana-Farber Cancer Institute
- Maria F. Suarez Peredo Rodriguez
- European Research Institute for the Biology of Ageing, University Medical Center Groningen
- Declan Whyte
- European Research Institute for the Biology of Ageing, University Medical Center Groningen
- Xiao Ling
- European Research Institute for the Biology of Ageing, University Medical Center Groningen
- Anouk van den Brink
- European Research Institute for the Biology of Ageing, University Medical Center Groningen
- Kaimeng Huang
- Broad Institute of Harvard and MIT
- Michelle Swift
- Department of Radiation Oncology, Dana-Farber Cancer Institute
- Yizhou He
- Broad Institute of Harvard and MIT
- Johanna Zerbib
- Department of Human Molecular Genetics & Biochemistry, Faculty of Medicine, Tel Aviv University
- Ross Smith
- Department of Immunology, Genetics and Pathology, Uppsala University
- Jonne Raaijmakers
- Oncode Institute, Division of Cell Biology, The Netherlands Cancer Institute
- Pratiti Bandopadhayay
- Harvard Medical School
- Lillian M. Guenther
- St. Jude Children’s Research Hospital, Department of Oncology
- Justin H. Hwang
- Division of Hematology, Oncology, and Transplantation, University of Minnesota
- Amanda Iniguez
- Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania
- Susan Moody
- Department of Medical Oncology and Center for Neuro-Oncology, Dana-Farber Cancer Institute
- Ji-Heui Seo
- Department of Medical Oncology and Center for Neuro-Oncology, Dana-Farber Cancer Institute
- Elizabeth H. Stover
- Department of Medical Oncology and Center for Neuro-Oncology, Dana-Farber Cancer Institute
- Levi Garraway
- Department of Medical Oncology and Center for Neuro-Oncology, Dana-Farber Cancer Institute
- William C. Hahn
- Department of Medical Oncology and Center for Neuro-Oncology, Dana-Farber Cancer Institute
- Kimberly Stegmaier
- Harvard Medical School
- René H. Medema
- Oncode Institute, Division of Cell Biology, The Netherlands Cancer Institute
- Dipanjan Chowdhury
- Broad Institute of Harvard and MIT
- Maria Colomé-Tatché
- Institute of Computational Biology, Helmholtz Munich
- Uri Ben-David
- Department of Human Molecular Genetics & Biochemistry, Faculty of Medicine, Tel Aviv University
- Rameen Beroukhim
- Department of Medical Oncology and Center for Neuro-Oncology, Dana-Farber Cancer Institute
- Floris Foijer
- European Research Institute for the Biology of Ageing, University Medical Center Groningen
- DOI
- https://doi.org/10.1038/s41467-025-56301-2
- Journal volume & issue
-
Vol. 16,
no. 1
pp. 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.
