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

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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.

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Journal

Journal ID (iso-abbrev): Cell

Title: Cell

ISSN (Electronic): 1097-4172

ISSN (Print): 0092-8674

Publication date (Electronic): Dec 3 2015

Volume: 163

Issue: 6

Affiliations

[1 ] Donnelly Centre, 160 College Street, Toronto, ON M5S3E1, Canada.

[2 ] Donnelly Centre, 160 College Street, Toronto, ON M5S3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A1, Canada.

[3 ] Department of Pharmaceutical Sciences and Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S1A1, Canada.

[4 ] The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, Canada.

[5 ] 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.

[6 ] 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.

[7 ] 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.

[8 ] 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.

[9 ] Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A1, Canada; The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, Canada.

[10 ] 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.

[11 ] 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.

Article

Publisher Item ID: S0092-8674(15)01495-6

DOI: 10.1016/j.cell.2015.11.015

PubMed ID: 26627737

SO-VID: 7515efd6-c526-4c65-b851-2e0d79077128

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