eLife (Feb 2017)
Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability
- Brenton R Paolella,
- William J Gibson,
- Laura M Urbanski,
- John A Alberta,
- Travis I Zack,
- Pratiti Bandopadhayay,
- Caitlin A Nichols,
- Pankaj K Agarwalla,
- Meredith S Brown,
- Rebecca Lamothe,
- Yong Yu,
- Peter S Choi,
- Esther A Obeng,
- Dirk Heckl,
- Guo Wei,
- Belinda Wang,
- Aviad Tsherniak,
- Francisca Vazquez,
- Barbara A Weir,
- David E Root,
- Glenn S Cowley,
- Sara J Buhrlage,
- Charles D Stiles,
- Benjamin L Ebert,
- William C Hahn,
- Robin Reed,
- Rameen Beroukhim
Affiliations
- Brenton R Paolella
- ORCiD
- 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 Gibson
- 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
- Laura M Urbanski
- 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
- John A Alberta
- Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States; Department of Neurobiology, Harvard Medical School, Boston, United States
- Travis I 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
- Pratiti 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; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States
- Caitlin A Nichols
- 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
- Pankaj K Agarwalla
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States
- Meredith S 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 Lamothe
- 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
- Yong Yu
- Department of Cell Biology, Harvard Medical School, Boston, United States
- Peter S Choi
- 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
- Esther A Obeng
- 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
- Dirk Heckl
- Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
- Guo Wei
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States
- Belinda Wang
- 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
- Aviad Tsherniak
- ORCiD
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States
- Francisca Vazquez
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States
- Barbara A Weir
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States
- David E Root
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States
- Glenn S Cowley
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States
- Sara J Buhrlage
- Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States
- Charles D Stiles
- Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States; Department of Neurobiology, Harvard Medical School, Boston, United States
- Benjamin L Ebert
- 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
- William C Hahn
- ORCiD
- 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
- Robin Reed
- Department of Cell Biology, Harvard Medical School, Boston, United States
- Rameen Beroukhim
- 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
- DOI
- https://doi.org/10.7554/eLife.23268
- Journal volume & issue
-
Vol. 6
Abstract
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 factor SF3B1, is also frequently mutated in cancer. We validated SF3B1 as a CYCLOPS gene and found that human cancer cells harboring partial SF3B1 copy-loss lack a reservoir of SF3b complex that protects cells with normal SF3B1 copy number from cell death upon partial SF3B1 suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-type SF3B1 as a novel, non-driver cancer gene dependency.
Keywords
- Copy number alterations
- Spliceosome
- SF3B1
- Target identification and validation
- CYCLOPS genes
- Cancer therapeutics
