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.
Authors
- Johanna Zerbib
- Anouk van den Brink (ORCID: https://orcid.org/0000-0003-1316-8673)
- Dipanjan Chowdhury (ORCID: https://orcid.org/0000-0001-5645-3752)
- Declan Whyte (ORCID: https://orcid.org/0009-0009-0705-2296)
- Kimberly Stegmaier (ORCID: https://orcid.org/0000-0003-0218-7895)
- Yizhou He (ORCID: https://orcid.org/0000-0002-1396-7275)
- Ji-Heui Seo (ORCID: https://orcid.org/0000-0002-7280-3334)
- Jonne A. Raaijmakers (ORCID: https://orcid.org/0000-0003-1759-8347)
- Uri Ben‐David (ORCID: https://orcid.org/0000-0001-7098-2378)
- Rameen Beroukhim (ORCID: https://orcid.org/0000-0001-6303-3609)
- Maria F. Suárez Peredo Rodríguez (ORCID: https://orcid.org/0000-0003-4414-0673)
- Susan E. Moody (ORCID: https://orcid.org/0009-0002-7714-1170)
- Levi A. Garraway (ORCID: https://orcid.org/0000-0003-3739-0471)
- Michaël Schubert (ORCID: https://orcid.org/0000-0002-6862-5221)
- Maria Colomé‐Tatché (ORCID: https://orcid.org/0000-0002-2224-7560)
- Elizabeth H. Stover (ORCID: https://orcid.org/0000-0002-6578-3216)
- William C. Hahn (ORCID: https://orcid.org/0000-0003-2840-9791)
- Michelle Swift (ORCID: https://orcid.org/0000-0003-3645-1308)
- Amanda Balboni Iniguez (ORCID: https://orcid.org/0000-0002-5048-0722)
- Verónica Rendo (ORCID: https://orcid.org/0000-0002-2983-4020)
- René H. Medema (ORCID: https://orcid.org/0000-0002-6754-0381)
- Kaimeng Huang (ORCID: https://orcid.org/0000-0002-0552-209X)
- Ross Smith (ORCID: https://orcid.org/0000-0003-4239-3204)
- Lillian M. Guenther (ORCID: https://orcid.org/0000-0002-5906-7504)
- Pratiti Bandopadhayay (ORCID: https://orcid.org/0000-0002-4175-4760)
- Floris Foijer (ORCID: https://orcid.org/0000-0003-0989-3127)
- Ling Xiao (ORCID: https://orcid.org/0000-0002-7439-0289)
- Justin H. Hwang (ORCID: https://orcid.org/0000-0003-1686-7103)
- Nicholas Khuu (ORCID: https://orcid.org/0009-0001-9967-1538)
Institutions
- Broad Institute (US)
- Uppsala University (SE)
- University of Minnesota (US)
- St. Jude Children's Research Hospital (US)
- University Medical Center Groningen (NL)
- Harvard University (US)
- Innsbruck Medical University (AT)
- Tel Aviv University (IL)
- Universität Innsbruck (AT)
- The Netherlands Cancer Institute (NL)
- Helmholtz Zentrum München (DE)
- Center for Neuro-Oncology (US)
- Oncode Institute (NL)
- Dana-Farber Cancer Institute (US)
- Dana-Farber/Harvard Cancer Center (US)
- University of Pennsylvania (US)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-01-27
- DOI
- https://doi.org/10.1038/s41467-025-56301-2
- Citations
- 13
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 10.48