Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Cell, 2015-12, Vol.163 (6), p.1515-1526

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Identification of 5-fold more fitness genes in human cells than previously observed•Core fitness genes are highly enriched for ancient protein complexes•Context-specific fitness genes illuminate biological differences between cell types•Distinct genetic signatures can be used to predict differential drug response CRISPR knockout screens for essential genes reveal oncogenic drivers specific to different cancer cell lines as well as unexpected metabolic and signaling dependencies that may guide future therapeutic targeting.