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

Nat Genet
Authors
Keywords
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.

Year of Publication
2017
Journal
Nat Genet
Volume
49
Issue
12
Pages
1779-1784
Date Published
2017 Dec
ISSN
1546-1718
DOI
10.1038/ng.3984
PubMed ID
29083409
PubMed Central ID
PMC5709193
Links
Grant list
P01 CA154303 / CA / NCI NIH HHS / United States
R01 CA130988 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
U01 CA199253 / CA / NCI NIH HHS / United States