A compendium of Amplification-Related Gain Of Sensitivity genes in human cancer
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.
Article Details
Authors (29)
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
Department of Pediatric Oncology, Dana-Farber Cancer Institute
René H. Medema
Dipanjan Chowdhury
Maria Colomé-Tatché
Uri Ben-David
Rameen Beroukhim
Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard
Floris Foijer