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Elife. 2017 Feb 8;6. pii: e23268. doi: 10.7554/eLife.23268.

Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability.

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.
2
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, United States.
3
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.
4
Department of Neurobiology, Harvard Medical School, Boston, United States.
5
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.
6
Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
7
Department of Cell Biology, Harvard Medical School, Boston, United States.
8
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
9
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States.

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:

CYCLOPS genes; Cancer therapeutics; Copy number alterations; SF3B1; Spliceosome; Target identification and validation; cancer biology; human; human biology; medicine; mouse

PMID:
28177281
PMCID:
PMC5357138
DOI:
10.7554/eLife.23268
[Indexed for MEDLINE]
Free PMC Article

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