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. 2022 May 16;12(9):4181–4199. doi: 10.7150/thno.73235

Figure 8.

Figure 8

A prognostic APOBEC mutagenesis-related model was established and validated, and potentially applicable drugs were screened for the high-risk subset. (A & B) After LASSO regularization (10-fold cross-validation, optimal λ = 0.022), 21 genes retained their Cox coefficients, and a prognostic APOBEC mutagenesis-related risk score (AMrs) was calculated for each BLCA patient. (C) The ridgeline plots showed that significant differences in the performances of various cancer hallmarks were observed between AMrs-low and AMrs-high samples. (D) In the training set (TCGA-BLCA), patients with higher AMrs exhibited worse CSS (HR = 3.570, 95% CI = 2.511-5.076, p < 0.0001). (E-G) The prognostic value of AMrs was validated for CSS in three independent BLCA cohorts (GSE13507: HR = 3.916, 95% CI = 1.946-7.879, p = 0.0003; GSE32894: HR = 8.242, 95% CI = 3.689-18.42, p < 0.0001; GSE48075: HR = 3.751, 95% CI = 1.487-9.466, p < 0.0001). (H) A total of 1,837 compounds from three drug response databases (GDSC, CTRP, and PRISM) were screened to identify potential therapeutic targets and compounds for patients with high AMrs. (I) For the GDSC database, Spearman correlation analysis was performed on AMrs and estimated IC50 values. With a filtering threshold of negative r value and p value less than 0.05, 12 candidate compounds were identified, and two compounds with most negative correlation coefficients were annotated as cell cycle inhibitors, namely BI-2536 and RO-3306. (J) The signaling pathways and therapeutic targets of the 12 candidate compounds from GDSC. (K & M) AUC values of compounds from CTRP and PRISM were estimated for each TCGA sample, and Spearman correlation analysis was performed on AMrs and estimated AUC values. For both CTRP and PRISM, five compounds with most negative correlation coefficients were displayed in dot-line plots (CTRP: PI-103, PYR-41, niclosamide, PIK-93, NSC 74859; PRISM: temocapril, AC-264613, pirenperone, oxymatrine, ruxolitinib), (L & N) and all estimated AUC values of these compounds were significantly lower in the AMrs-high group. *** p < 0.001.