Fig. 2

Transcriptomics scores reflecting phenocopying events can identify causal genes in CNA-affected chromosomal segments. a Prioritization score of genes for TP53 loss phenocopying effects. Y axis shows gene significance (FDR) when combining six statistical tests (four cancer genomic/transcriptomic, and two based on CRISPR and RNAi screens), and further pooling p-values across cancer types; see Methods for details. X axis represents the effect size specifically from the CRISPR codependency test score of a gene. Crosses represent gene neighbours (same cytoband) to a known phenocopying gene. Above-threshold hits in terms of FDR and codependency score are labelled. Shown thresholds (dashed lines) for effect size and significance were determined based on scores of known phenocopy events (CRISPR score = -0.21, FDR = 4e-5, according to MDM4 score in LUAD, see Methods). Genes with a pan-cancer CRISPR or RNAi codependecy score lower than 0.1 were filtered out. Same figure but showing the RNAi codependency score on X axis is provided in Additional file 1: Fig. S4b. b Top: CNV frequency in tumors, and their associations with TP53 phenocopy transcriptomic scores, in the segment of chromosome 1 containing MDM4. Each dot represents one gene, while colours represent groups of tumor samples by TP53 status. Bottom: A zoomed-in view of a commonly amplified region of the chromosome, showing the CRISPR and the RNAi TP53-codependency scores for each gene. The data underlying the TP53 codependency score is shown for the top-ranking score of the region (left panels), here showing the CRISPR and RNAi fitness effects of MDM4 disruption (Y axis) across many cell lines (dots), compared to TP53 disruption fitness effects (X axis) across the same cell lines. c Same as panel b, but for USP28, a gene we identified to be associated with a TP53 loss phenocopying via a deletion. Here, the Y axis on the top plot shows frequency of gene deletions in tumors, subdivided by TP53 functional status, whereas panel b shows frequency of amplification. Bottom plots are analogous to  panel b. d Comparison of the TP53 phenocopy score of USP28 CNV deletions (by negative GISTIC score), ATM deletions, ATM mutations and MDM4 amplifications. Each dot represents a tumor sample. Only TP53 wild-type samples were considered. P-values by Mann–Whitney test. e Fitness effect of USP28 knock-out in TP53 wild-type and mutant isogenic cell lines. Comparison of the mean beta score (fitness effect upon CRISPR gene disruption, y-axis) of USP28. , The mean beta scores of genes located within its 1Mbp immediate surroundings are shown as negative controls ("1 Mbp neighbors", see Methods). Genes TP53, MDM2, and MDM4 are also shown as a reference. x-axis bottom labels indicate the TP53 status of the cell line. The USP28 Z-scores, comparing to the distribution of neighbouring genes, are plotted in red (see Methods)