Analysis of CRISPR-Cas9 datasets leads to largest genetic screen resource for cancer research
Study will help narrow down the list of targets for the next generation of cancer treatments
A comprehensive map of genes necessary for cancer survival is one step closer, following the validation of the two largest CRISPR-Cas9 genetic screens in 725 cancer models, across 25 different cancer types. Scientists at the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard compared the consistency of the two datasets, independently verifying the methodology and findings.
The results, published today (20 December 2019) in Nature Communications, mean that the two datasets can be integrated to form the largest genetic screen of cancer cell lines to date, which will provide the basis for the Cancer Dependency Map in around 1,000 cancer models. The scale of this combined dataset will help to speed up the discovery and development of new cancer drugs.
The Cancer Dependency Map (Cancer DepMap) initiative* aims to create a detailed rulebook of precision cancer treatments for patients. Two key elements of the Cancer DepMap are the mapping of the genes critical for the survival of cancer cells and analytics of the resulting datasets. Despite recent advances in cancer research, making precision medicine widely available to cancer patients requires many new drug targets.
To find these drug targets, Cancer DepMap researchers take tumour cells from patients to create cell lines that can be grown in the laboratory. They then use CRISPR-Cas9 technology to edit the genes in these cancer cells, turning them off one-by-one to measure how critical they are for the cancer to survive. The results of these experiments indicate which genes are the most likely to make viable drug targets.
In this new study, researchers analysed data from two recently published CRISPR-Cas9 genetic screens performed on cancer cell lines at the Broad and Sanger Institutes. Despite significant differences in experimental protocols, the team found that the screen results were consistent with one another. Crucially, the same genes essential to cancer survival – known as dependencies – were found in both datasets.
“The Sanger and Broad Institute CRISPR-Cas9 screens were created using slightly different protocols, such as cell growth duration and reagents used. To verify each Institute’s dataset, we have repeated CRISPR-Cas9 screens using the protocols originally employed at the other Institute. Importantly, we have found the same genetic dependencies in each, meaning the new drug targets originally identified are consistent.”
“This is the first analysis of its kind and is really important for the whole cancer research community. Not only have we reproduced common and specific dependencies across the two datasets, but we have taken biomarkers of gene dependency found in one dataset and recovered them in the other. Our analysis has been unbiased, rigorous and proves the veracity of the approach and the drug targets identified.”
Aviad Tsherniak Of the Broad Institute of MIT and Harvard
In 2013, results comparing two large pharmacogenomic datasets employing the cancer models used in this study raised concerns about the reproducibility of the experiments performed. Further independently-published analyses eventually proved the two resources to be reliable and consistent, restoring confidence in the robustness of large-scale drug screens, but the episode slowed the progress of cancer research.
This study validates the reproducibility of CRISPR-Cas9 functional genetic screens in order to remove any doubt about their efficacy. It sets rigorous standards for assessing these new types of dataset, facilitating the comparison and integration of large databases of cancer dependencies.
“It is worth remembering that when these datasets were originally produced we were dealing with a new, unproven technology. This study is important because it demonstrates the validity of the experimental methods and the consistency of the data that they produce. It also means that two large cancer dependency datasets are compatible. By joining them together, we will have access to much greater statistical power to narrow down the list of targets for the next generation of cancer treatments.”
* Mapping the dependencies of cancers is an international effort by the Sanger Institute in the UK and the Broad Institute in the United States. Researchers aim to bridge the translational gap that exists between genomic sequencing and providing precision medicine to the many cancer patients. Genes that are critical to a cancer’s survival represent dependencies: vulnerabilities that might serve as targets for designing new therapies or repurposing existing ones. Mapping these dependencies is essential to making precision cancer medicine a reality.
Joshua M. Dempster, Clare Pacini and Sasha Pantel et al. (2019) Agreement between two large pan-cancer CRISPR-Cas9 gene dependency datasets. Nature Communications. DOI: https://www.doi.org/10.1038/s41467-019-13805-y
This work was funded by Open Targets, Wellcome, the Estonian Research Council and the HL Snyder Foundation.
Open Targets is a pioneering public-private collaboration that aims to transform drug discovery through the systematic identification and prioritisation of drug targets to improve the success rate for developing new medicines. The consortium is a unique, pre-competitive partnership between pharmaceutical companies and not-for-profit research institutes. The partners are GSK, Biogen, Takeda, Celgene, Sanofi, the Wellcome Sanger Institute and the EMBL’s European Bioinformatics Institute (EMBL-EBI). Open Targets combines the skills, knowledge and technologies of its partner organisations, offering a critical mass of expertise that does not exist in any single institution. Large-scale genomic experiments and computational techniques developed in the public domain are blended with formal pharmaceutical R&D approaches to identify causal links between targets, pathways and diseases. This enables the partners to systematically identify drug targets, and prioritise them for further exploration. Find more at https://www.opentargets.org/science/ or follow @targetvalidate
Broad Institute of MIT and Harvard was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods, and data openly to the entire scientific community. Founded by MIT, Harvard, Harvard-affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff, and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to https://www.broadinstitute.org
The Wellcome Sanger Institute is a world leading genomics research centre. We undertake large-scale research that forms the foundations of knowledge in biology and medicine. We are open and collaborative; our data, results, tools and technologies are shared across the globe to advance science. Our ambition is vast – we take on projects that are not possible anywhere else. We use the power of genome sequencing to understand and harness the information in DNA. Funded by Wellcome, we have the freedom and support to push the boundaries of genomics. Our findings are used to improve health and to understand life on Earth. Find out more at www.sanger.ac.uk or follow us on Twitter, Facebook, LinkedIn and on our Blog.
Wellcome exists to improve health by helping great ideas to thrive. We support researchers, we take on big health challenges, we campaign for better science, and we help everyone get involved with science and health research. We are a politically and financially independent foundation. https://wellcome.org/
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