Extended Data Fig. 2: Variants modulating drug sensitivity cluster into four functional classes.

a) Base editor screens in H23, PC9 and MHH-ES-1 cancer cells targeting 11 cancer genes show depletion of gRNAs targeting essential genes demonstrating base editing activity. Unpaired, two-tailed Student’s t-test comparing non-targeting gRNAs (n = 114) to gRNAs targeting essential gene splice sites (n = 632) in CBE and ABE screens. For MHH-ES-1, ABE screens are shown (NT; n = 57; essential-targeting, n = 306). Boxplots represent the median and interquartile range (IQR), and whiskers represent the lowest and highest values within 1.5 x the IQR. b) Number of off-target sites plotted against the z-score for base editing gRNAs. A high number of off-targets for a small number of KRAS UTR-targeting gRNAs is associated with severe gRNA depletion. These were filtered out of downstream analysis. c)Our previously reported whole-genome CRISPR-Cas9 KO screen in HT-29 cells in the presence of dabrafenib (0.1 µM) across three time-points. Volcano plot showing EGFR KO as the top sensitising hit. Data are the average of two independent screens and significance was determined with MAGeCK, with a threshold of p-value < 0.05 and FDR < 0.05. d)TCGA oncoprint (pan-cancer cohort, n = 526) of colorectal adenocarcinomas with alterations in KRAS and BRAF. Mutual exclusivity p-value < 0.001 derived from two-sided Fisher exact test, q-value < 0.001 derived from Benjamini-Hochberg FDR correction procedure for multiple hypothesis testing.