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Cancer vulnerabilities unveiled by genomic loss |
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| Authors: | Deepak Nijhawan Travis I Zack Yin Ren Matthew R Strickland Rebecca Lamothe Steven E Schumacher Aviad Tsherniak Henrike C Besche Joseph Rosenbluh Shyemaa Shehata Glenn S Cowley Barbara A Weir Alfred L Goldberg Jill P Mesirov David E Root Sangeeta N Bhatia Rameen Beroukhim William C Hahn |
| Affiliation: | 1 Departments of Cancer Biology and Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA 2 Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA 3 Biophysics Program, Harvard University, Boston, MA 02115, USA 4 Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA 5 Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA 6 David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA 7 Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA 8 Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA |
| Abstract: | Due to genome instability, most cancers exhibit loss of regions containing tumor suppressor genes and collateral loss of other genes. To identify cancer-specific vulnerabilities that are the result of copy number losses, we performed integrated analyses of genome-wide copy number and RNAi profiles and identified 56 genes for which gene suppression specifically inhibited the proliferation of cells harboring partial copy number loss of that gene. These CYCLOPS (copy number alterations yielding cancer liabilities owing to partial loss) genes are enriched for spliceosome, proteasome, and ribosome components. One CYCLOPS gene, PSMC2, encodes an essential member of the 19S proteasome. Normal cells express excess PSMC2, which resides in?a complex with PSMC1, PSMD2, and PSMD5 and acts as a reservoir protecting cells from PSMC2 suppression. Cells harboring partial PSMC2 copy number loss lack this complex and die after PSMC2 suppression. These observations define a distinct class of cancer-specific liabilities resulting from genome instability. |
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