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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Veröffentlicht in:	Cell Jg. 163; H. 6; S. 1515
Hauptverfasser:	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
Sprache:	Englisch
Veröffentlicht:	United States 03.12.2015
Schlagworte:	Bayes Theorem Cell Line, Tumor CRISPR-Cas Systems Gene Knockout Techniques Gene Library Genes, Essential Humans Mutation
ISSN:	1097-4172, 1097-4172
Online-Zugang:	Weitere Angaben
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Abstract	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.
AbstractList	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.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. 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.
Author	Durocher, Daniel Moffat, Jason Sidhu, Sachdev Mis, Monika Aregger, Michael Fradet-Turcotte, Amelie Roth, Frederick P Rissland, Olivia S Steinhart, Zachary Angers, Stephane Chandrashekhar, Megha Sun, Song Hart, Traver Mero, Patricia Dirks, Peter Brown, Kevin R MacLeod, Graham Zimmermann, Michal
Author_xml	– sequence: 1 givenname: Traver surname: Hart fullname: Hart, Traver organization: Donnelly Centre, 160 College Street, Toronto, ON M5S3E1, Canada – sequence: 2 givenname: Megha surname: Chandrashekhar fullname: Chandrashekhar, Megha organization: Donnelly Centre, 160 College Street, Toronto, ON M5S3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A1, Canada – sequence: 3 givenname: Michael surname: Aregger fullname: Aregger, Michael organization: Donnelly Centre, 160 College Street, Toronto, ON M5S3E1, Canada – sequence: 4 givenname: Zachary surname: Steinhart fullname: Steinhart, Zachary organization: Department of Pharmaceutical Sciences and Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S1A1, Canada – sequence: 5 givenname: Kevin R surname: Brown fullname: Brown, Kevin R organization: Donnelly Centre, 160 College Street, Toronto, ON M5S3E1, Canada – sequence: 6 givenname: Graham surname: MacLeod fullname: MacLeod, Graham organization: Department of Pharmaceutical Sciences and Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S1A1, Canada – sequence: 7 givenname: Monika surname: Mis fullname: Mis, Monika organization: Department of Pharmaceutical Sciences and Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S1A1, Canada – sequence: 8 givenname: Michal surname: Zimmermann fullname: Zimmermann, Michal organization: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, Canada – sequence: 9 givenname: Amelie surname: Fradet-Turcotte fullname: Fradet-Turcotte, Amelie organization: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, Canada – sequence: 10 givenname: Song surname: Sun fullname: Sun, Song organization: Donnelly Centre, 160 College Street, Toronto, ON M5S3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A1, Canada; Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala SE-75123, Sweden; Department of Computer Science, University of Toronto, Toronto, ON M5G1X8, Canada – sequence: 11 givenname: Patricia surname: Mero fullname: Mero, Patricia organization: Donnelly Centre, 160 College Street, Toronto, ON M5S3E1, Canada – sequence: 12 givenname: Peter surname: Dirks fullname: Dirks, Peter organization: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A1, Canada; Program in Developmental and Stem Cell Biology, Division of Neurosurgery, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G1X8, Canada – sequence: 13 givenname: Sachdev surname: Sidhu fullname: Sidhu, Sachdev organization: Donnelly Centre, 160 College Street, Toronto, ON M5S3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A1, Canada – sequence: 14 givenname: Frederick P surname: Roth fullname: Roth, Frederick P organization: Donnelly Centre, 160 College Street, Toronto, ON M5S3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A1, Canada; The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5G1X8, Canada; Canadian Institute for Advanced Research, Toronto, ON M5G1Z8, Canada; Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA – sequence: 15 givenname: Olivia S surname: Rissland fullname: Rissland, Olivia S organization: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A1, Canada; Molecular Structure and Function Program, The Hospital for Sick Children Research Institute, 686 Bay Street, Toronto, ON M5G0A4, Canada – sequence: 16 givenname: Daniel surname: Durocher fullname: Durocher, Daniel organization: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A1, Canada; The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, Canada – sequence: 17 givenname: Stephane surname: Angers fullname: Angers, Stephane organization: Department of Pharmaceutical Sciences and Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S1A1, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S1A1, Canada – sequence: 18 givenname: Jason surname: Moffat fullname: Moffat, Jason email: j.moffat@utoronto.ca organization: Donnelly Centre, 160 College Street, Toronto, ON M5S3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A1, Canada; Canadian Institute for Advanced Research, Toronto, ON M5G1Z8, Canada. Electronic address: j.moffat@utoronto.ca
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/26627737$$D View this record in MEDLINE/PubMed
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SubjectTerms	Bayes Theorem Cell Line, Tumor CRISPR-Cas Systems Gene Knockout Techniques Gene Library Genes, Essential Humans Mutation
Title	High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities
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