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Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells.
Nat Genet. 2017 Dec; 49(12):1779-1784.NGen

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.

Links

Authors+Show Affiliations

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Boston Children's Hospital, Boston, Massachusetts, USA. Harvard Medical School, Boston, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Boston Children's Hospital, Boston, Massachusetts, USA. Harvard Medical School, Boston, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Boston Children's Hospital, Boston, Massachusetts, USA. Harvard Medical School, Boston, Massachusetts, USA. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Harvard Medical School, Boston, Massachusetts, USA. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

MeSH

AlgorithmsCRISPR-Cas SystemsCell Line, TumorComputational BiologyDNA Copy Number VariationsGene DosageGenetic Predisposition to DiseaseHumansModels, GeneticNeoplasmsReproducibility of ResultsSensitivity and Specificity

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29083409

Citation

Meyers, Robin M., et al. "Computational Correction of Copy Number Effect Improves Specificity of CRISPR-Cas9 Essentiality Screens in Cancer Cells." Nature Genetics, vol. 49, no. 12, 2017, pp. 1779-1784.

Meyers RM, Bryan JG, McFarland JM, et al. Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells. Nat Genet. 2017;49(12):1779-1784.

Meyers, R. M., Bryan, J. G., McFarland, J. M., Weir, B. A., Sizemore, A. E., Xu, H., Dharia, N. V., Montgomery, P. G., Cowley, G. S., Pantel, S., Goodale, A., Lee, Y., Ali, L. D., Jiang, G., Lubonja, R., Harrington, W. F., Strickland, M., Wu, T., Hawes, D. C., ... Tsherniak, A. (2017). Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells. Nature Genetics, 49(12), 1779-1784. https://doi.org/10.1038/ng.3984

Meyers RM, et al. Computational Correction of Copy Number Effect Improves Specificity of CRISPR-Cas9 Essentiality Screens in Cancer Cells. Nat Genet. 2017;49(12):1779-1784. PubMed PMID: 29083409.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells. AU - Meyers,Robin M, AU - Bryan,Jordan G, AU - McFarland,James M, AU - Weir,Barbara A, AU - Sizemore,Ann E, AU - Xu,Han, AU - Dharia,Neekesh V, AU - Montgomery,Phillip G, AU - Cowley,Glenn S, AU - Pantel,Sasha, AU - Goodale,Amy, AU - Lee,Yenarae, AU - Ali,Levi D, AU - Jiang,Guozhi, AU - Lubonja,Rakela, AU - Harrington,William F, AU - Strickland,Matthew, AU - Wu,Ting, AU - Hawes,Derek C, AU - Zhivich,Victor A, AU - Wyatt,Meghan R, AU - Kalani,Zohra, AU - Chang,Jaime J, AU - Okamoto,Michael, AU - Stegmaier,Kimberly, AU - Golub,Todd R, AU - Boehm,Jesse S, AU - Vazquez,Francisca, AU - Root,David E, AU - Hahn,William C, AU - Tsherniak,Aviad, Y1 - 2017/10/30/ PY - 2017/04/07/received PY - 2017/10/04/accepted PY - 2017/10/31/pubmed PY - 2017/12/12/medline PY - 2017/10/31/entrez SP - 1779 EP - 1784 JF - Nature genetics JO - Nat Genet VL - 49 IS - 12 N2 - 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. SN - 1546-1718 UR - https://www.unboundmedicine.com/medline/citation/29083409/Computational_correction_of_copy_number_effect_improves_specificity_of_CRISPR_Cas9_essentiality_screens_in_cancer_cells_ DB - PRIME DP - Unbound Medicine ER -