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Nat Genet. 2017 Dec;49(12):1779-1784. doi: 10.1038/ng.3984. Epub 2017 Oct 30.

Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells.

Author information

1
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
2
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
3
Boston Children's Hospital, Boston, Massachusetts, USA.
4
Harvard Medical School, Boston, Massachusetts, USA.
5
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
6
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Abstract

The CRISPR-Cas9 system has revolutionized gene editing both at single genes and in multiplexed loss-of-function screens, thus enabling precise genome-scale identification of genes essential for proliferation and survival of cancer cells. However, previous studies have reported that a gene-independent antiproliferative effect of Cas9-mediated DNA cleavage confounds such measurement of genetic dependency, thereby leading to false-positive results in copy number-amplified regions. We developed CERES, a computational method to estimate gene-dependency levels from CRISPR-Cas9 essentiality screens while accounting for the copy number-specific effect. In our efforts to define a cancer dependency map, we performed genome-scale CRISPR-Cas9 essentiality screens across 342 cancer cell lines and applied CERES to this data set. We found that CERES decreased false-positive results and estimated sgRNA activity for both this data set and previously published screens performed with different sgRNA libraries. We further demonstrate the utility of this collection of screens, after CERES correction, for identifying cancer-type-specific vulnerabilities.

PMID:
29083409
PMCID:
PMC5709193
DOI:
10.1038/ng.3984
[Indexed for MEDLINE]
Free PMC Article

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