High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities

The ability to perturb genes in human cells is crucial for elucidating gene function and holds great potential for finding therapeutic targets for diseases such as cancer. To extend the catalog of human core and context-dependent fitness genes, we have developed a high-complexity second-generation g...

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Published in:Cell Vol. 163; no. 6; p. 1515
Main Authors: Hart, Traver, Chandrashekhar, Megha, Aregger, Michael, Steinhart, Zachary, Brown, Kevin R, MacLeod, Graham, Mis, Monika, Zimmermann, Michal, Fradet-Turcotte, Amelie, Sun, Song, Mero, Patricia, Dirks, Peter, Sidhu, Sachdev, Roth, Frederick P, Rissland, Olivia S, Durocher, Daniel, Angers, Stephane, Moffat, Jason
Format: Journal Article
Language:English
Published: United States 03.12.2015
Subjects:
Bayes Theorem
Cell Line, Tumor
CRISPR-Cas Systems
Gene Knockout Techniques
Gene Library
Genes, Essential
Humans
Mutation
ISSN:1097-4172, 1097-4172
Online Access:Get more information
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Summary:The ability to perturb genes in human cells is crucial for elucidating gene function and holds great potential for finding therapeutic targets for diseases such as cancer. To extend the catalog of human core and context-dependent fitness genes, we have developed a high-complexity second-generation genome-scale CRISPR-Cas9 gRNA library and applied it to fitness screens in five human cell lines. Using an improved Bayesian analytical approach, we consistently discover 5-fold more fitness genes than were previously observed. We present a list of 1,580 human core fitness genes and describe their general properties. Moreover, we demonstrate that context-dependent fitness genes accurately recapitulate pathway-specific genetic vulnerabilities induced by known oncogenes and reveal cell-type-specific dependencies for specific receptor tyrosine kinases, even in oncogenic KRAS backgrounds. Thus, rigorous identification of human cell line fitness genes using a high-complexity CRISPR-Cas9 library affords a high-resolution view of the genetic vulnerabilities of a cell.
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2015.11.015