Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability
- Dana-Farber Cancer Institute, Harvard Medical School, United States
- Harvard Medical School, United States
- Brigham and Women's Hospital, Harvard Medical School, United States
- Massachusetts Institute of Technology and Harvard University, 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.
Data availability
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Effect of SF3B1 suppression in cancer cells with different SF3B1 copy-number levelsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE81978).
Article and author information
Author details
Brenton R Paolella
Funding
National Cancer Institute (F32 CA180653)
- Brenton R Paolella
National Cancer Institute (P50 CA165962)
- Charles D Stiles
The Sontag Foundation
- Rameen Beroukhim
The Grey Matters Foundation
- Rameen Beroukhim
The Pediatric Low Grade Astrocytoma Foundation
- Pratiti Bandopadhayay
- Charles D Stiles
- Rameen Beroukhim
Friends for Life Fellowship
- Brenton R Paolella
National Cancer Institute (R01 CA188228)
- Rameen Beroukhim
National Cancer Institute (U01 CA176058)
- William C Hahn
National Cancer Institute (F30 CA192725)
- William J Gibson
National Institute of General Medical Sciences (R01 GM043375)
- Robin Reed
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Michael R Green, Howard Hughes Medical Institute, University of Massachusetts Medical School, United States
Ethics
Animal experimentation: This work was conducted in accordance with and approved by the institutional animal care and use committee (IACUC) protocols (#15-014) of the Dana-Farber Cancer Institute.
Version history
- Received: November 14, 2016
- Accepted: February 6, 2017
- Accepted Manuscript published: February 8, 2017 (version 1)
- Version of Record published: March 17, 2017 (version 2)
Copyright
© 2017, Paolella et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability
eLife 6:e23268.
https://doi.org/10.7554/eLife.23268
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