A compendium of Amplification-Related Gain Of Sensitivity genes in human cancer PMID: 39870664

ADC Targets in Oncology

2026-04-10

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

1. Department of Medical Oncology and Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
3. Harvard Medical School, Boston, MA, USA. [email protected].
4. Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected].
5. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. [email protected].
6. Oncode Institute, Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, Netherlands. [email protected].
7. European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, Netherlands. [email protected].
8. Institute of Computational Biology, Helmholtz Munich, Neuherberg, Germany. [email protected].
9. Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. [email protected].
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. [email protected].
26. Department of Medical Oncology and Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
27. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
28. Harvard Medical School, Boston, MA, USA. [email protected].
29. Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected].
30. European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, Netherlands. [email protected].
# Contributed equally.

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.