Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells
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Abstract
The CRISPR-Cas9 system has revolutionized gene editing both at single genes and in multiplexed loss-of-function screens, thus enabling precise genome-scale identification of genes essential for proliferation and survival of cancer cells. However, previous studies have reported that a gene-independent antiproliferative effect of Cas9-mediated DNA cleavage confounds such measurement of genetic dependency, thereby leading to false-positive results in copy number-amplified regions. We developed CERES, a computational method to estimate gene-dependency levels from CRISPR-Cas9 essentiality screens while accounting for the copy number-specific effect. In our efforts to define a cancer dependency map, we performed genome-scale CRISPR-Cas9 essentiality screens across 342 cancer cell lines and applied CERES to this data set. We found that CERES decreased false-positive results and estimated sgRNA activity for both this data set and previously published screens performed with different sgRNA libraries. We further demonstrate the utility of this collection of screens, after CERES correction, for identifying cancer-type-specific vulnerabilities.
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Co-essential genes were determined from Wainberg et al., 2019, which scored co-essentiality across genome-wide CRISPR screens in 485 cancer cell lines.
“Co-essential genes were determined from Wainberg et al., 2019, which scored co-essentiality of genes across genome-wide CRISPR screens in 485 cancer cell lines (Meyers et al., 2017) using a generalized least-squares regression.”
From Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma (2020) · cites this paper as Meyers et al., 2017
The paper’s Abstract (page unavailable) says Meyers et al. performed genome-scale CRISPR-Cas9 screens in 342 cancer cell lines, supporting the identification of the screening dataset. It does not support the cited figure of 485 cell lines. The sentence attributes the co-essentiality scoring method to Wainberg et al., not to Meyers et al. (LLM, conf=0.90)
Experimental — accuracy not yet measuredm6A modifications are most enriched in the 3′ untranslated region (UTR), with significant concentrations also found near the stop codon in the coding sequence (CDS).
“Along the length of mRNAs, m6A modifications are not uniformly distributed. These modifications are most enriched in the 3′ untranslated region (UTR), with significant concentrations also found near the stop codon in the coding sequence (CDS) [29,30].”
From IMPlications of IMP2 in RNA Biology and Disease (2025) · cites this paper as [29]
The Online Methods section on sgRNA genome mapping discusses CRISPR guide sequences and gene coding sequences, not m6A distribution. Searches for m6A enrichment, the 3′ UTR, and stop codons found no passage in our copy addressing the claim. (LLM, conf=0.78)
Experimental — accuracy not yet measuredVHL is essential in 935 of the profiled cell lines.
“Despite its well-established role as a tumor suppressor in renal carcinoma25, VHL proved essential in 935 of the profiled cell lines.”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [24]
CRBN is a non-essential gene across 1070 cell lines profiled by genome-scale CRISPR/Cas9 knockout screens.
“Mining publicly available data from the DepMap Consortium, CRBN presents as a non-essential gene across 1070 cell lines that were profiled via genome-scale CRISPR/Cas9 knockout screens (Fig. 1A)24.”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [24]
According to the cancer dependency map, which provides gene essentiality derived from CRISPR-knockout studies across more than 340 cancer cell lines and multiple cancer types, a number of E3 ligases are essential in most cancer types.
“According to the cancer dependency map (depmap.org), which provides gene essentiality derived from CRISPR-knockout studies across >340 cancer cell lines and multiple cancer types 61 , a number of E3 ligases are essential - and therefore available for proteasome-targeting applications - in most cancer types (Fig. 3c).”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [61]
The recommended threshold below which a gene is considered essential is -1.
“The recommended threshold below which a gene is considered essential is -1 (ref. 61 ).”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [61]
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- [20]Tsherniak A Vazquez F Golub TR Boehm JS Hahn WC Defining a Cancer Dependency Map Cell 1 31 2017 10.1016/j.cell.2017.06.010 PMC5667678 28753430 · DOI · Paper page
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- Authors
- Meyers, R. M., Bryan, J. G., McFarland, J. M., Weir, B. A., Sizemore, A. E., Xu, H., Dharia, N. V., Montgomery, P. G., Cowley, G. S., Pantel, S., Goodale, A., Lee, Y., Ali, L. D., Jiang, G., Lubonja, R., Harrington, W. F., Strickland, M., Wu, T., Hawes, D. C., Zhivich, V. A., Wyatt, M. R., Kalani, Z., Chang, J. J., Okamoto, M., Stegmaier, K., Golub, T. R., Boehm, J. S., Vazquez, F., Root, D. E., Hahn, W. C., & Tsherniak, A.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Hahn, William C
- Tsherniak, Aviad
- ORCID
- Meyers, Robin M
- Bryan, Jordan G
- McFarland, James M
- Sizemore, Ann E
- Xu, Han
- Dharia, Neekesh V
- Montgomery, Phillip G
- Cowley, Glenn S
- Goodale, Amy
- Lee, Yenarae
- Ali, Levi D
- Jiang, Guozhi
- Strickland, Matthew
- Wu, Ting
- Wyatt, Meghan R
- Kalani, Zohra
- Stegmaier, Kimberly
- Golub, Todd R
- Boehm, Jesse S
- Root, David E
- Hahn, William C
- Tsherniak, Aviad
- Venue
- Nature Genetics
- Published
- 2017-10-30
- Volume
- 49
- Issue
- 12
- Pages
- 1779-1784
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5709193
- OpenAlex
- W2735132087
- Cited by
- 1,952
- References
- 29
- Citations by year
- 2026: 130 · 2025: 216 · 2024: 274 · 2023: 258 · 2022: 298 · 2021: 313 · 2020: 229 · 2019: 152 · 2018: 70 · 2017: 8 · 2014: 1 · 2013: 1
- FWCI
- 52.12
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Cancer Institute (U01CA176058, P01CA154303, U01CA199253, R01CA130988)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- Ceres, false positive reduction, cancer cell lines, DepMap
- MeSH terms
- Algorithms, Humans, Models, Genetic, Neoplasms, Sensitivity and Specificity, Reproducibility of Results, Gene Dosage, Computational Biology, Genetic Predisposition to Disease, Cell Line, Tumor, DNA Copy Number Variations, CRISPR-Cas Systems
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