Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability.
Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent. One of these, the pre-mRNA splicing factorSF3B1, is also frequently mutated in cancer. We validatedSF3B1as a CYCLOPS gene and found that human cancer cells harboring partialSF3B1copy-loss lack a reservoir of SF3b complex that protects cells with normalSF3B1copy number from cell death upon partialSF3B1suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-typeSF3B1as a novel, non-driver cancer gene dependency.
Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.|Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.
Brenton R
0000-0003-3394-828X
BR
Paolella
Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.|Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.
William J
WJ
Gibson
Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.
Laura M
LM
Urbanski
Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.|Department of Neurobiology, Harvard Medical School, Boston, United States.
John A
JA
Alberta
Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.|Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.
Travis I
TI
Zack
Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.|Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.|Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.
Pratiti
P
Bandopadhayay
Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.|Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.
Caitlin A
CA
Nichols
Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
Pankaj K
PK
Agarwalla
Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.
Meredith S
MS
Brown
Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.
Rebecca
R
Lamothe
Department of Cell Biology, Harvard Medical School, Boston, United States.
Yong
Y
Yu
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.
Peter S
PS
Choi
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States.|Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
Esther A
EA
Obeng
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
Dirk
D
Heckl
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States.
Guo
G
Wei
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.
Belinda
B
Wang
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States.
Aviad
0000-0002-3797-1877
A
Tsherniak
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States.
Francisca
F
Vazquez
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States.
Barbara A
BA
Weir
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States.
David E
DE
Root
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States.
Glenn S
GS
Cowley
Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.
Sara J
SJ
Buhrlage
Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.|Department of Neurobiology, Harvard Medical School, Boston, United States.
Charles D
CD
Stiles
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States.|Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
Benjamin L
BL
Ebert
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States.
William C
0000-0003-2840-9791
WC
Hahn
Department of Cell Biology, Harvard Medical School, Boston, United States.
Robin
R
Reed
Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.|Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States.
Rameen
R
Beroukhim
D045744:Cell Line, Tumor; D018628:Gene Dosage; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D010750:Phosphoproteins / Q000235:genetics*; D000072260:RNA Splicing Factors / Q000235:genetics*
D010750:Phosphoproteins; D000072260:RNA Splicing Factors; C112491:SF3B1 protein, human
CYCLOPS genes; Cancer therapeutics; Copy number alterations; SF3B1; Spliceosome; Target identification and validation; cancer biology; human; human biology; medicine; mouse