Partial gene suppression improves identification of cancer vulnerabilities when CRISPR-Cas9 knockout is pan-lethal

BackgroundHundreds of functional genomic screens have been performed across a diverse set of cancer contexts, as part of efforts such as the Cancer Dependency Map, to identify gene dependencies—genes whose loss of function reduces cell viability or fitness. Recently, large-scale screening efforts ha...

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Published inGenome Biology Vol. 24; no. 1; pp. 1 - 192
Main Authors Krill-Burger, J. Michael, Dempster, Joshua M., Borah, Ashir A., Paolella, Brenton R., Root, David E., Golub, Todd R., Boehm, Jesse S., Hahn, William C., McFarland, James M., Vazquez, Francisca, Tsherniak, Aviad
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Published London BioMed Central 23.08.2023
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Abstract BackgroundHundreds of functional genomic screens have been performed across a diverse set of cancer contexts, as part of efforts such as the Cancer Dependency Map, to identify gene dependencies—genes whose loss of function reduces cell viability or fitness. Recently, large-scale screening efforts have shifted from RNAi to CRISPR-Cas9, due to superior efficacy and specificity. However, many effective oncology drugs only partially inhibit their protein targets, leading us to question whether partial suppression of genes using RNAi could reveal cancer vulnerabilities that are missed by complete knockout using CRISPR-Cas9. Here, we compare CRISPR-Cas9 and RNAi dependency profiles of genes across approximately 400 matched cancer cell lines.ResultsWe find that CRISPR screens accurately identify more gene dependencies per cell line, but the majority of each cell line’s dependencies are part of a set of 1867 genes that are shared dependencies across the entire collection (pan-lethals). While RNAi knockdown of about 30% of these genes is also pan-lethal, approximately 50% have selective dependency patterns across cell lines, suggesting they could still be cancer vulnerabilities. The accuracy of the unique RNAi selectivity is supported by associations to multi-omics profiles, drug sensitivity, and other expected co-dependencies.ConclusionsIncorporating RNAi data for genes that are pan-lethal knockouts facilitates the discovery of a wider range of gene targets than could be detected using the CRISPR dataset alone. This can aid in the interpretation of contrasting results obtained from CRISPR and RNAi screens and reinforce the importance of partial gene suppression methods in building a cancer dependency map.
AbstractList BACKGROUNDHundreds of functional genomic screens have been performed across a diverse set of cancer contexts, as part of efforts such as the Cancer Dependency Map, to identify gene dependencies-genes whose loss of function reduces cell viability or fitness. Recently, large-scale screening efforts have shifted from RNAi to CRISPR-Cas9, due to superior efficacy and specificity. However, many effective oncology drugs only partially inhibit their protein targets, leading us to question whether partial suppression of genes using RNAi could reveal cancer vulnerabilities that are missed by complete knockout using CRISPR-Cas9. Here, we compare CRISPR-Cas9 and RNAi dependency profiles of genes across approximately 400 matched cancer cell lines.RESULTSWe find that CRISPR screens accurately identify more gene dependencies per cell line, but the majority of each cell line's dependencies are part of a set of 1867 genes that are shared dependencies across the entire collection (pan-lethals). While RNAi knockdown of about 30% of these genes is also pan-lethal, approximately 50% have selective dependency patterns across cell lines, suggesting they could still be cancer vulnerabilities. The accuracy of the unique RNAi selectivity is supported by associations to multi-omics profiles, drug sensitivity, and other expected co-dependencies.CONCLUSIONSIncorporating RNAi data for genes that are pan-lethal knockouts facilitates the discovery of a wider range of gene targets than could be detected using the CRISPR dataset alone. This can aid in the interpretation of contrasting results obtained from CRISPR and RNAi screens and reinforce the importance of partial gene suppression methods in building a cancer dependency map.
Abstract Background Hundreds of functional genomic screens have been performed across a diverse set of cancer contexts, as part of efforts such as the Cancer Dependency Map, to identify gene dependencies—genes whose loss of function reduces cell viability or fitness. Recently, large-scale screening efforts have shifted from RNAi to CRISPR-Cas9, due to superior efficacy and specificity. However, many effective oncology drugs only partially inhibit their protein targets, leading us to question whether partial suppression of genes using RNAi could reveal cancer vulnerabilities that are missed by complete knockout using CRISPR-Cas9. Here, we compare CRISPR-Cas9 and RNAi dependency profiles of genes across approximately 400 matched cancer cell lines. Results We find that CRISPR screens accurately identify more gene dependencies per cell line, but the majority of each cell line’s dependencies are part of a set of 1867 genes that are shared dependencies across the entire collection (pan-lethals). While RNAi knockdown of about 30% of these genes is also pan-lethal, approximately 50% have selective dependency patterns across cell lines, suggesting they could still be cancer vulnerabilities. The accuracy of the unique RNAi selectivity is supported by associations to multi-omics profiles, drug sensitivity, and other expected co-dependencies. Conclusions Incorporating RNAi data for genes that are pan-lethal knockouts facilitates the discovery of a wider range of gene targets than could be detected using the CRISPR dataset alone. This can aid in the interpretation of contrasting results obtained from CRISPR and RNAi screens and reinforce the importance of partial gene suppression methods in building a cancer dependency map.
ArticleNumber 192
Author Krill-Burger, J Michael
McFarland, James M
Root, David E
Vazquez, Francisca
Tsherniak, Aviad
Boehm, Jesse S
Paolella, Brenton R
Hahn, William C
Dempster, Joshua M
Golub, Todd R
Borah, Ashir A
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Snippet BackgroundHundreds of functional genomic screens have been performed across a diverse set of cancer contexts, as part of efforts such as the Cancer Dependency...
BACKGROUNDHundreds of functional genomic screens have been performed across a diverse set of cancer contexts, as part of efforts such as the Cancer Dependency...
Abstract Background Hundreds of functional genomic screens have been performed across a diverse set of cancer contexts, as part of efforts such as the Cancer...
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StartPage 1
SubjectTerms Cancer
Cancer genomics
Cell viability
CRISPR
CRISPR-Cas systems
CRISPR-Cas9 genome editing
Datasets
Experiments
Functional genomics
Genes
Genomes
Mutation
Reagents
RNA-mediated interference
RNAi
Target identification
Tumor cell lines
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Title Partial gene suppression improves identification of cancer vulnerabilities when CRISPR-Cas9 knockout is pan-lethal
URI https://www.proquest.com/docview/2865407634
https://search.proquest.com/docview/2857848317
https://pubmed.ncbi.nlm.nih.gov/PMC10464129
https://doaj.org/article/1c92c0bab42244fc81f9b12dd6f2049f
Volume 24
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