The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.
CRISPR Screens Provide a Comprehensive Assessment of Cancer Vulnerabilities but Generate False-Positive Hits for Highly Amplified Genomic Regions
Abstract
CRISPR/Cas9 has emerged as a powerful new tool to systematically probe gene function. We compared the performance of CRISPR to RNAi-based loss-of-function screens for the identification of cancer dependencies across multiple cancer cell lines. CRISPR dropout screens consistently identified more lethal genes than RNAi, implying that the identification of many cellular dependencies may require full gene inactivation. However, in two aneuploid cancer models, we found that all genes within highly amplified regions, including nonexpressed genes, scored as lethal by CRISPR, revealing an unanticipated class of false-positive hits. In addition, using a CRISPR tiling screen, we found that sgRNAs targeting essential domains generate the strongest lethality phenotypes and thus provide a strategy to rapidly define the protein domains required for cancer dependence. Collectively, these findings not only demonstrate the utility of CRISPR screens in the identification of cancer-essential genes, but also reveal the need to carefully control for false-positive results in chromosomally unstable cancer lines. Significance: We show in this study that CRISPR-based screens have a significantly lower false-negative rate compared with RNAi-based screens, but have specific liabilities particularly in the interrogation of regions of genome amplification. Therefore, this study provides critical insights for applying CRISPR-based screens toward the systematic identification of new cancer targets. Cancer Discov; 6(8); 900–13. ©2016 AACR. See related commentary by Sheel and Xue, p. 824. See related article by Aguirre et al., p. 914. This article is highlighted in the In This Issue feature, p. 803
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Cites
Multiplex Genome Engineering Using CRISPR/Cas Systems
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The Pfam Protein Families Database
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RNA-Guided Human Genome Engineering via Cas9
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The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
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Self-citationDevelopment and Applications of CRISPR-Cas9 for Genome Engineering
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Genetic screens in human cells using the CRISPR-Cas9 system
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Genome-Scale CRISPR-Mediated Control of Gene Repression and Activation
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GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases
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Dynamic Imaging of Genomic Loci in Living Human Cells by an Optimized CRISPR/Cas System
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Cited by
Defining a Cancer Dependency Map
Tsherniak, A., Vazquez, F., Montgomery, P. G., Weir, B. A., Kryukov, G., Cowley, G. S., Gill, S., Harrington, W. F., Pantel, S., Krill-Burger, J. M., et al. (2017) · Cell · doi:10.1016/j.cell.2017.06.010 · Cited by 3,276
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Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens
Behan, F. M., Iorio, F., Picco, G., Gonçalves, E., Beaver, C. M., Migliardi, G., Santos, R., Rao, Y., Sassi, F., Pinnelli, M., et al. (2019) · Nature · doi:10.1038/s41586-019-1103-9 · Cited by 1,338
Genome-scale CRISPR-Cas9 Knockout and Transcriptional Activation Screening
Joung, J., Konermann, S., Gootenberg, J. S., Abudayyeh, O. O., Platt, R. J., Brigham, M. D., Sanjana, N. E., & Zhang, F. (2017) · Nature Protocols · doi:10.1038/nprot.2017.016 · Cited by 1,243
p53 inhibits CRISPR–Cas9 engineering in human pluripotent stem cells
Ihry, R. J., Worringer, K. A., Salick, M. R., Frias, E., Ho, D., Theriault, K., Kommineni, S., Chen, J., Sondey, M., Ye, C., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0050-6 · Cited by 978
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Metadata
- Authors
- Munoz, D. M., Cassiani, P. J., Li, L., Billy, E., Korn, J. M., Jones, M. D., Golji, J., Ruddy, D. A., Yu, K., McAllister, G., DeWeck, A., Abramowski, D., Wan, J., Shirley, M. D., Neshat, S. Y., Rakiec, D., de Beaumont, R., Weber, O., Kauffmann, A., McDonald, E. R., Keen, N., Hofmann, F., Sellers, W. R., Schmelzle, T., Stegmeier, F., & Schlabach, M. R.
- Venue
- Cancer Discovery
- Published
- 2016-08-01
- Volume
- 6
- Issue
- 8
- Pages
- 900-913
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2411238967
- Cited by
- 359
- References
- 32
- FWCI
- 22.72
- Type
- journal article
- Language
- en
- Open access
- closed
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- Munoz, D. M., Cassiani, P. J., Li, L., Billy, E., Korn, J. M., Jones, M. D., Golji, J., Ruddy, D. A., Yu, K., McAllister, G., DeWeck, A., Abramowski, D., Wan, J., Shirley, M. D., Neshat, S. Y., Rakiec, D., de Beaumont, R., Weber, O., Kauffmann, A., . . . Schlabach, M. R. (2016). CRISPR Screens Provide a Comprehensive Assessment of Cancer Vulnerabilities but Generate False-Positive Hits for Highly Amplified Genomic Regions. Cancer Discovery. https://doi.org/10.1158/2159-8290.cd-16-0178
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