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Cell DOI:10.1016/j.cell.2012.07.023

Cancer vulnerabilities unveiled by genomic loss.

Publication TypeJournal Article
Year of Publication2012
AuthorsNijhawan, D, Zack, TI, Ren, Y, Strickland, MR, Lamothe, R, Schumacher, SE, Tsherniak, A, Besche, HC, Rosenbluh, J, Shehata, S, Cowley, GS, Weir, BA, Goldberg, AL, Mesirov, JP, Root, DE, Bhatia, SN, Beroukhim, R, Hahn, WC
Date Published2012 Aug 17
KeywordsAnimals, Cell Line, Tumor, Chromosome Deletion, Gene Dosage, Genes, Essential, Genes, Tumor Suppressor, Genomic Instability, Humans, Mice, Mice, Nude, Neoplasm Transplantation, Neoplasms, Proteasome Endopeptidase Complex, Transplantation, Heterologous

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.


Alternate JournalCell
PubMed ID22901813
PubMed Central IDPMC3429351
Grant ListR01 GM051923-17 / GM / NIGMS NIH HHS / United States
U54 CA143798 / CA / NCI NIH HHS / United States
U54 CA151884 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
K08 CA122833 / CA / NCI NIH HHS / United States
R01 CA109467 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
T32 GM008313 / GM / NIGMS NIH HHS / United States
U54 CA112962 / CA / NCI NIH HHS / United States
RC2 CA148268 / CA / NCI NIH HHS / United States
P01 CA050661 / CA / NCI NIH HHS / United States