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.
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.
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
Further reading
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Why does a normal cell possibly harboring genetic mutations in oncogene or tumor suppressor genes becomes malignant and develops a tumor is a subject of intense debate. Various theories have been proposed but their experimental test has been hampered by the unpredictable and improbable malignant transformation of single cells. Here, using an optogenetic approach we permanently turn on an oncogene (KRASG12V) in a single cell of a zebrafish brain that, only in synergy with the transient co-activation of a reprogramming factor (VENTX/NANOG/OCT4), undergoes a deterministic malignant transition and robustly and reproducibly develops within 6 days into a full-blown tumor. The controlled way in which a single cell can thus be manipulated to give rise to cancer lends support to the ‘ground state theory of cancer initiation’ through ‘short-range dispersal’ of the first malignant cells preceding tumor growth.
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