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

Verónica Rendo; Michaël Schubert; Nicholas Khuu; Maria F. Suárez Peredo Rodríguez; Declan Whyte; Xiao Ling; Anouk van den Brink; Kaimeng Huang; Michelle L. Swift; Yizhou Joseph He; Johanna Zerbib; Ross Smith; Jonne A. Raaijmakers; Pratiti Bandopadhayay; Lillian M. Guenther; Justin H. Hwang; Amanda Balboni Iniguez; Susan E. Moody; Ji-Heui Seo; Elizabeth H. Stover; Levi A. Garraway; William C. Hahn; Kimberly Stegmaier; René H. Medema; Dipanjan Chowdhury; Maria Colomé‐Tatché; Uri Ben‐David; Rameen Beroukhim; Floris Foijer

doi:10.1038/s41467-025-56301-2

Cancer BiologyNature CommunicationsJan 27, 2025

Peer-reviewed journal article

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

Verónica Rendo iD, Michaël Schubert iD, Nicholas Khuu iD, Maria F. Suárez Peredo Rodríguez iD, Declan Whyte iD, Xiao Ling iD, Anouk van den Brink iD, Kaimeng Huang iD, Michelle L. Swift iD, Yizhou Joseph He iD, Johanna Zerbib iD, Ross Smith iD, Jonne A. Raaijmakers iD, Pratiti Bandopadhayay iD, Lillian M. Guenther iD, Justin H. Hwang iD, Amanda Balboni Iniguez iD, Susan E. Moody iD, Ji-Heui Seo iD, Elizabeth H. Stover iD, Levi A. Garraway iD, William C. Hahn iD, Kimberly Stegmaier iD, René H. Medema iD, Dipanjan Chowdhury iD, , Floris Foijer iD

Abstract

Chromosomal gains are among the most frequent somatic genetic alterations occurring in cancer. While the effect of sustained oncogene expression has been characterized, the impact of copy-number gains affecting collaterally-amplified "bystander" genes on cellular fitness remains less understood. To investigate this, we built a comprehensive map of dosage compensations across human cancers by integrating expression and copy number profiles from over 8,000 TCGA tumors and CCLE cell lines. Further, we analyzed the effect of gene overexpression across 17 human cancer ORF screens to provide an overview of genes that prove toxic to cancer cells when overexpressed. Combining these two independent approaches we propose a class of Amplification-Related Gain Of Sensitivity (ARGOS) genes. These genes are located in commonly amplified regions of the genome, have lower expression levels than expected by their copy-number status, and are toxic to cancer cells when overexpressed. We experimentally validated CDKN1A and RBM14 as high-confidence pan-cancer ARGOS genes in lung and breast cancer cell line models. We additionally suggest that RBM14s mechanism of toxicity involves altered DNA damage response and innate immune signaling processes following gene overexpression. Finally, we provide a comprehensive catalog of compensated, toxic, and ARGOS genes as a community resource.

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