Fig. 3: Detecting robust associations between genetic or epigenetic markers and drug sensitivity by replication across measurements.
From: Mutational signatures are markers of drug sensitivity of cancer cells
a A schematic of the randomization test methodology to detect replicating associations using three different tests: (i) consistent effects of a drug between two screening assays (GDSC/PRISM), (ii) effects of a drug consistent with effects of knockout of the target gene (GDSC/PSCORE), and (iii) effects consistent across different drugs that share the same molecular target (GDSC/GDSC or “same target”). Box plots and scatterplot are illustrative. b–d Examples of replicated associations of a known example of oncogene addiction (to BRAF, b) and of additional cancer vulnerabilities associated with mutations in tumor suppressor genes (ARID1A, c; TP53 d). Y-axes show a Z-score derived from either the ln IC50 value (i.e. drug sensitivity, in columns labeled “GDSC” or “PRISM”) or from the CRISPR essentiality score (in the column labeled “PSCORE”). Horizontal brackets show FDR for replicated significant difference between wild-type and mutant genotypes, obtained via a randomization test in panel a, where color denotes the type of the replication test (“GDSC”, “PRISM” or “PSCORE”). The center line of box plots denotes medians and the hinges correspond to the 1st and 3rd quartiles, while whiskers extend to 1.5× IQR from the hinges. e, Effect sizes of markers that associate with drug response in the GDSC drug screen (X-axes) and with response drug target gene knock-out in the Project SCORE genetic screen (Y-axes), shown separately for copy number alterations (CNA) and mutations in cancer genes (Muts). Gray points represent all tested associations, while colored points denote the statistically significant associations that also meet an effect size threshold. Blue lines are the contours of the 2D kernel density estimates. Representative points are labeled. Drug names on grouped labels (“Muts” sub-panel) are ordered by their appearance on the plot from left to right. Source data are provided as a Source Data file.
