Fig. 6: CAAs shape drug response and outperform other genomic events in response prediction.

a Heatmap of Spearman correlations between CAA burden and a pharmacogenomic predictor of pathologic complete response (pCR) to preoperative paclitaxel and fluorouracil-doxorubicin-cyclophosphamide (T/FAC) chemotherapy. Numbers in tiles show q values, i.e., FDR-corrected significance from Fisher’s exact tests, as Fig. 2b. Ns, not significant (q > 0.05). b Sunburst plot showing the distribution of pharmacogenomic alterations used in our machine learning model, including 285 high-confidence cancer genes (GCs), 425 recurrently copy number-altered chromosomal segments (RACSs), collectively referred to as cancer functional events (CFEs), and 78 CAAs. c Bubble volcano plot showing how specific CFEs and CAAs alter response to anti-cancer drugs, as determined by elastic net regression. The impact is shown as Glass’ Δ log₁₀(IC₅₀) effect size between cell lines with and without the alteration. Bubble colours correspond to cancer types. Bubble sizes are proportional to the numbers of cell lines. Selected CFEs and CAAs are highlighted in blue and red, respectively. Two CAA-drug interactions can be explained by focal CNAs (*). d Beeswarm plots showing the extent to which several CAAs significantly increase drug resistance or sensitivity. Cell lines negative (−) and positive (+) for indicated CAAs are shown. Horizontal lines represent the mean IC₅₀ value. See Supplementary Data 10 for full data. e Tukey boxplot showing the fractions of CFEs or CAAs that significantly alter drug response. Shown are the medians with interquartile ranges and all data points. Lines connect the respective fractions for each of the 22 cancer types. P value: Paired Wilcoxon signed-rank test. f Summary table showing the performance of machine learning models based on CFEs alone, CAAs alone and CFEs and CAAs combined. g Beeswarm plot showing the differences between the F₁ performance scores from the CFE-based and the CAA-based models for each of the tested 39 drugs. Mean and 95% confidence interval are shown. P values: one sample t-test (top), Fisher’s exact test (right). Source data are provided as a Source Data file.