Integrative analysis of large-scale loss-of-function screens identifies robust cancer-associated genetic interactions
- Breast Cancer Now Toby Robins Research Centre and Cancer Research UK Gene Function Laboratory, Institute of Cancer Research, United Kingdom
- School of Computer Science and Systems Biology Ireland, University College Dublin, Ireland
Figures
Figure 1
Identifying robust genetic interactions using partially overlapping loss-of-function screens.
(A) Workflow showing the integration of four different loss-of-function screen datasets. (B) Venn diagram showing the overlap of cell lines between the four datasets analysed in this study. (C) …
Figure 2 with 1 supplement
Discovered and validated genetic dependencies.
(A) Scatterplot showing the genetic dependencies identified across all datasets. Each individual point represents a gene pair, the x-axis shows the common language effect size, and the y-axis shows …
Figure 2—figure supplement 1
Discovered and validated genetic dependencies for individual datasets.
(A) Scatterplot showing the genetic dependencies identified in the SCORE dataset. Each individual point represents a gene pair, the x-axis shows the common language effect size, and the y-axis shows …
Figure 3 with 1 supplement
Identified robust genetic interactions.
(A) Dot plot showing the robust genetic dependencies identified for oncogenes. Each coloured circle indicates a robust genetic dependency, scaled according to the number of dataset pairs it was …
Figure 3—figure supplement 1
Reproducible genetic dependencies include oncogene addictions.
(A) Dot plot showing the reproducible genetic dependencies identified. Each coloured circle indicates a reproducible genetic dependency, scaled according to the number of dataset pairs it was …
Figure 4
Robust genetic interactions involving RB1 and BRAF recapitulate pathway relationships.
(A) Simplified RAS/RAF/MEK/ERK pathway diagram. Protein names (e.g. MEK) are shown inside nodes, while associated gene names are shown adjacent (e.g. MAP2K1). Nodes are coloured according to their …
Figure 5 with 2 supplements
Robust genetic interactions are enriched in protein–protein interaction pairs.
(A) Barchart showing the percentage of protein–protein interacting pairs observed among different groups of gene pairs. The groups represent all gene pairs tested, gene pairs found to be …
Figure 5—figure supplement 1
Robust genetic interactions are enriched in protein–protein interaction pairs at different thresholds and using different databases.
(A) Barchart showing the percentage of protein–protein interacting pairs observed among different groups of gene pairs. The groups represent all gene pairs tested, gene pairs found to be …
Figure 5—figure supplement 2
Genetic interactions are more enriched in real protein–protein interaction networks than randomised networks.
Histograms showing the overlap between 100 degree matched randomisations of the STRING medium confidence protein–protein interaction and discovered (A and B) and validated (C and D) genetic …
Figure 6
Reproducible ATR synthetic lethal interactions are enriched in ATR protein–protein interaction partners.
(A) Workflow - synthetic lethal interactions from CRISPR-Cas9 screens in three cell lines (Wang et al., 2019) were compared to identify reproducible synthetic lethal partners. These genes were then …
Figure 7
Robust synthetic lethalities associated with passenger gene loss.
(A) Boxplots showing the association between VPS4B loss and VPS4A sensitivity in the discovery dataset (DRIVE) and two validation datasets (AVANA and SCORE). (B) Mean viability of HAP1 cells treated …
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Additional files
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Supplementary file 1
Driver gene alterations.
- https://cdn.elifesciences.org/articles/58925/elife-58925-supp1-v3.csv
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Supplementary file 2
Selectively lethal genes.
- https://cdn.elifesciences.org/articles/58925/elife-58925-supp2-v3.txt
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Supplementary file 3
Reproducible genetic dependencies.
- https://cdn.elifesciences.org/articles/58925/elife-58925-supp3-v3.xlsx
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Supplementary file 4
Pathway enrichment of driver gene dependencies.
- https://cdn.elifesciences.org/articles/58925/elife-58925-supp4-v3.xlsx
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Supplementary file 5
Protein–protein interaction enrichment.
- https://cdn.elifesciences.org/articles/58925/elife-58925-supp5-v3.xlsx
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Supplementary file 6
Passenger gene loss alterations.
- https://cdn.elifesciences.org/articles/58925/elife-58925-supp6-v3.csv
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Supplementary file 7
Passenger gene dependencies.
- https://cdn.elifesciences.org/articles/58925/elife-58925-supp7-v3.csv
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Supplementary file 8
VPS4A_VPS4B and DDX5_DDX17 viability data.
- https://cdn.elifesciences.org/articles/58925/elife-58925-supp8-v3.xlsx
