Cancer vulnerabilities unveiled by genomic loss.
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.
Departments of Cancer Biology and Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
Deepak
D
Nijhawan
Travis I
TI
Zack
Yin
Y
Ren
Matthew R
MR
Strickland
Rebecca
R
Lamothe
Steven E
SE
Schumacher
Aviad
A
Tsherniak
Henrike C
HC
Besche
Joseph
J
Rosenbluh
Shyemaa
S
Shehata
Glenn S
GS
Cowley
Barbara A
BA
Weir
Alfred L
AL
Goldberg
Jill P
JP
Mesirov
David E
DE
Root
Sangeeta N
SN
Bhatia
Rameen
R
Beroukhim
William C
WC
Hahn
D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D018628:Gene Dosage; D020043:Genes, Essential; D016147:Genes, Tumor Suppressor; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
C075363:PSMC2 protein, human; D046988:Proteasome Endopeptidase Complex; C119011:26S proteasome non-ATPase regulatory subunit 13; D000074183:ATPases Associated with Diverse Cellular Activities