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Integrated cross-study datasets of genetic dependencies in cancer

Clare Pacini, View ORCID ProfileJoshua M. Dempster, Isabella Boyle, View ORCID ProfileEmanuel Gonçalves, View ORCID ProfileHanna Najgebauer, View ORCID ProfileEmre Karakoc, View ORCID ProfileDieudonne van der Meer, Andrew Barthorpe, View ORCID ProfileHoward Lightfoot, Patricia Jaaks, James M. McFarland, Mathew J. Garnett, View ORCID ProfileAviad Tsherniak, View ORCID ProfileFrancesco Iorio
doi: https://doi.org/10.1101/2020.05.22.110247
Clare Pacini
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
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Joshua M. Dempster
3Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA
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  • ORCID record for Joshua M. Dempster
Isabella Boyle
3Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA
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Emanuel Gonçalves
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
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  • ORCID record for Emanuel Gonçalves
Hanna Najgebauer
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
4European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
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  • ORCID record for Hanna Najgebauer
Emre Karakoc
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
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  • ORCID record for Emre Karakoc
Dieudonne van der Meer
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
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  • ORCID record for Dieudonne van der Meer
Andrew Barthorpe
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
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Howard Lightfoot
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
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  • ORCID record for Howard Lightfoot
Patricia Jaaks
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
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James M. McFarland
3Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA
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Mathew J. Garnett
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
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Aviad Tsherniak
3Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA
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Francesco Iorio
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
5Human Technopole, Via Cristina Belgioioso 147, 20157 Milano - Italy
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  • ORCID record for Francesco Iorio
  • For correspondence: francesco.iorio@sanger.ac.uk
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Abstract

CRISPR-Cas9 viability screens are increasingly performed at a genome-wide scale across large panels of cell lines to identify new therapeutic targets for precision cancer therapy. Integrating the datasets resulting from these studies is necessary to adequately represent the heterogeneity of human cancers and to assemble a comprehensive map of cancer genetic vulnerabilities. Here, we integrated the two largest public independent CRISPR-Cas9 screens performed to date (at the Broad and Sanger institutes) by assessing, comparing, and selecting methods for correcting biases due to heterogeneous single guide RNA efficiency, gene-independent responses to CRISPR-Cas9 targeting originated from copy number alterations, and experimental batch effects. Our integrated datasets recapitulate findings from the individual datasets, provide greater statistical power to cancer- and subtype-specific analyses, unveil additional biomarkers of gene dependency, and improve the detection of common essential genes. We provide the largest integrated resources of CRISPR-Cas9 screens to date and the basis for harmonizing existing and future functional genetics datasets.

Competing Interest Statement

MJG, and FI receive funding from Open Targets, a public-private initiative involving academia and industry. MJG receives funding from AstraZeneca and performs consultancy for Sanofi. FI performs consultancy for the joint CRUK - AstraZeneca Functional Genomics Centre. AT is a consultant `for Tango Therapeutics and Cedilla Therapeutics. JMD, JM and AT receive funding from the Cancer Dependency Map Consortium, but no consortium member was involved in or influenced this study. All the other authors declare no competing interests.

Footnotes

  • We have substantially restructured the Results section of our manuscript, reporting outcomes from a number of use case scenarios and highlighting pros and cons of each benchmarked computational method. This provides a results-driven decision making process that underpins our presentation of two distinct final integrated datasets of cancer dependencies, and demonstrates that this will be advantageous for the computational biology community. Additionally, we have carefully addressed all the other reviewers' points and also included a final novel analysis estimating the minimal required size of overlapping cell lines for integrating future CRISPR datasets.

  • https://depmap.org/broad-sanger/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 06, 2021.
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Integrated cross-study datasets of genetic dependencies in cancer
Clare Pacini, Joshua M. Dempster, Isabella Boyle, Emanuel Gonçalves, Hanna Najgebauer, Emre Karakoc, Dieudonne van der Meer, Andrew Barthorpe, Howard Lightfoot, Patricia Jaaks, James M. McFarland, Mathew J. Garnett, Aviad Tsherniak, Francesco Iorio
bioRxiv 2020.05.22.110247; doi: https://doi.org/10.1101/2020.05.22.110247
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Integrated cross-study datasets of genetic dependencies in cancer
Clare Pacini, Joshua M. Dempster, Isabella Boyle, Emanuel Gonçalves, Hanna Najgebauer, Emre Karakoc, Dieudonne van der Meer, Andrew Barthorpe, Howard Lightfoot, Patricia Jaaks, James M. McFarland, Mathew J. Garnett, Aviad Tsherniak, Francesco Iorio
bioRxiv 2020.05.22.110247; doi: https://doi.org/10.1101/2020.05.22.110247

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