TY - JOUR
T1 - High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities
AU - Hart, Traver
AU - Chandrashekhar, Megha
AU - Aregger, Michael
AU - Steinhart, Zachary
AU - Brown, Kevin R.
AU - MacLeod, Graham
AU - Mis, Monika
AU - Zimmermann, Michal
AU - Fradet-Turcotte, Amelie
AU - Sun, Song
AU - Mero, Patricia
AU - Dirks, Peter
AU - Sidhu, Sachdev
AU - Roth, Frederick P.
AU - Rissland, Olivia S.
AU - Durocher, Daniel
AU - Angers, Stephane
AU - Moffat, Jason
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/12/3
Y1 - 2015/12/3
N2 - 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.
AB - 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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U2 - 10.1016/j.cell.2015.11.015
DO - 10.1016/j.cell.2015.11.015
M3 - Article
C2 - 26627737
AN - SCOPUS:84949233942
SN - 0092-8674
VL - 163
SP - 1515
EP - 1526
JO - Cell
JF - Cell
IS - 6
ER -