Cancer Vulnerabilities Unveiled by Genomic Loss
Menée sur 86 lignées cellulaires de cancer et à partir de données portant sur 3 131 échantillons tumoraux, cette étude identifie des gènes dont dépendent les cellules cancéreuses qui, en raison d'une instabilité génomique, ont par ailleurs subi une perte de gènes suppresseurs de tumeurs
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. º Partial copy number loss renders cancer cells dependent on CYCLOPS genes º CYCLOPS genes are enriched for components of the proteasome, including PSMC2 º Copy number loss of PSMC2 leads to lower expression and loss of a PSMC2 reservoir º Targeting PSMC2 disrupts tumor maintenance in a genotype-specific manner Reducing the mRNA levels of genes that have suffered copy number loss due to genomic instability in cancer cells leads to tumor-cell-specific growth inhibition. Thus, probing cancer genomes for genes that have copy number losses can reveal new therapeutic targets.
Cell 2012