shinyDepMap, a tool to identify targetable cancer genes and their functional connections from Cancer Dependency Map data
Abstract
Individual cancers rely on distinct essential genes for their survival. The Cancer Dependency Map (DepMap) is an ongoing project to uncover these gene dependencies in hundreds of cancer cell lines. To make this drug discovery resource more accessible to the scientific community we built an easy-to-use browser, shinyDepMap (https://labsyspharm.shinyapps.io/depmap). shinyDepMap combines CRISPR and shRNA data to determine, for each gene, the growth reduction caused by knockout/knockdown and the selectivity of this effect across cell lines. The tool also clusters genes with similar dependencies, revealing functional relationships. shinyDepMap can be used to 1) predict the efficacy and selectivity of drugs targeting particular genes; 2) identify maximally sensitive cell lines for testing a drug; 3) target hop, i.e., navigate from an undruggable protein with the desired selectivity profile, such as an activated oncogene, to more druggable targets with a similar profile; and 4) identify novel pathways driving cancer cell growth and survival.
Data availability
Data files have been provided for Figures 1, 3, 4, and 5 on FigShare: https://figshare.com/projects/shinyDepMap_Source_Data/97382 (DOIs: 10.6084/m9.figshare.13653251.v1, 10.6084/m9.figshare.13653257.v1, 10.6084/m9.figshare.13653260.v1, 10.6084/m9.figshare.13653266.v1, 10.6084/m9.figshare.13653272.v1, 10.6084/m9.figshare.13653278.v1, 10.6084/m9.figshare.13653281.v2)
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shinyDepMap - Source Data 1FigShare, doi:10.6084/m9.figshare.13653251.
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shinyDepMap - Source Data 2FigShare, doi:10.6084/m9.figshare.13653257.v1.
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shinyDepMap - Source Data 3FigShare, doi:10.6084/m9.figshare.13653260.v1.
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shinyDepMap - Source Data 4FigShare, doi:10.6084/m9.figshare.13653266.v1.
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shinyDepMap - Source Data 5FigShare, doi:10.6084/m9.figshare.13653272.v1.
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shinyDepMap - Source Data 6FigShare, doi:10.6084/m9.figshare.13653278.v1.
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shinyDepMap - Source Data 7FigShare, doi:10.6084/m9.figshare.13653281.v2.
Article and author information
Author details
Funding
Japan Society for the Promotion of Science (H29-814)
- Kenichi Shimada
National Institute of General Medical Sciences (R35GM131753)
- Timothy J Mitchison
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Shimada et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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- Cancer Biology
- Genetics and Genomics
Interpretation of variants identified during genetic testing is a significant clinical challenge. In this study, we developed a high-throughput CDKN2A functional assay and characterized all possible human CDKN2A missense variants. We found that 17.7% of all missense variants were functionally deleterious. We also used our functional classifications to assess the performance of in silico models that predict the effect of variants, including recently reported models based on machine learning. Notably, we found that all in silico models performed similarly when compared to our functional classifications with accuracies of 39.5–85.4%. Furthermore, while we found that functionally deleterious variants were enriched within ankyrin repeats, we did not identify any residues where all missense variants were functionally deleterious. Our functional classifications are a resource to aid the interpretation of CDKN2A variants and have important implications for the application of variant interpretation guidelines, particularly the use of in silico models for clinical variant interpretation.
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