Ansah, E. O. | Search bioRxiv

bioRxiv2026

Genomic Correlates of APOBEC-Associated Mutagenesis in Esophageal Squamous Cell Carcinoma

Background and Aims: APOBEC-associated mutagenesis is prominent in esophageal squamous cell carcinoma (ESCC), but genomic features associated with its intertumoral variability remain incompletely characterized. We investigated genomic correlates of APOBEC-associated mutagenesis while accounting for the compositional structure of mutational signature data. Methods: Mutational signatures were analyzed in 552 ESCC tumors from eight countries. APOBEC-associated mutagenesis was quantified as SBS2 plus SBS13 using absolute mutation counts and proportional contributions. Associations with co-occurring mutational signatures, total SBS burden, recurrent driver-gene alterations, and country were evaluated using correlation, sensitivity, and multivariable analyses. Principal component and regression-model robustness were additionally assessed. Results: APOBEC burden varied markedly across tumors (median, 2,002 mutations; IQR, 987-4,346). Several associations observed using signature proportions were not maintained in absolute-count analyses: SBS1, SBS3, and SBS5 changed direction, indicating sensitivity to compositional representation. In contrast, SBS18 remained inversely associated with APOBEC-associated mutagenesis in all variable pairings examined: proportion versus proportion (Spearman rho = -0.527), APOBEC proportion versus SBS18 absolute count (r = -0.435), and absolute count versus absolute count (Pearson r = -0.319, P = 1.59 x 10^-14; Spearman rho = -0.317). These are distinct comparisons rather than discrepant estimates. Notably, this cohort-wide relationship was primarily characterized by higher APOBEC burden in SBS18-negative than SBS18-positive tumors rather than a continuous inverse relationship among SBS18-positive tumors. The multivariable model had an in-sample R^2 of 0.400 but lower and variable 10-fold cross-validated performance (mean R^2 = 0.273). Country added little explanatory information to this model (delta R^2 = 0.008; global P = 0.402). ZNF750-mutant tumors had higher APOBEC burden than wild-type tumors (BH-FDR q = 0.0032), although only 12 tumors carried ZNF750 alterations. Conclusion: Genomic correlates of APOBEC-associated mutagenesis in ESCC are sensitive to the representation of mutational signature activity. SBS18 showed the most consistent inverse association, whereas the ZNF750 association warrants independent validation.

genomics↗

bioRxiv2025

Hepatoprotective Effects of Vernonia amygdalina Leaf Extract: In Vivo and In Silico Evidence Against Ethanol-Induced Liver Injury

Alcoholic liver disease (ALD) remains a major global health burden with limited therapeutic options. In this study, we investigated the hepatoprotective effects of Vernonia amygdalina (VA) leaf extract against ethanol-induced liver injury using integrated in vivo and in silico approaches. Wistar rats were exposed to ethanol to induce liver damage, followed by treatment with VA extract (100-300 mg/kg) or silymarin (50 mg/kg). Liver function indices were evaluated through biochemical analysis. Network pharmacology analysis was performed to identify active compounds and their protein targets, and molecular docking assessed the binding affinities of key compounds. Ethanol exposure markedly increased serum SGOT, SGPT, ALKP, and total bilirubin while decreasing total protein and albumin. VA treatment significantly corrected these alterations in a dose-dependent manner. At 300 mg/kg, VA reduced SGPT from 110.31 to 88.65 U/mL, ALKP from 52.20 to 28.14 U/mL, and total bilirubin from 1.19 to 0.59 g/dL. Network pharmacology revealed flavonoids and sesquiterpene lactones as key active compounds targeting ALD-relevant proteins, including AKT1, CASP3, and HSP90AA1. Molecular docking demonstrated strong binding affinities (-9.5 kcal/mol) of cryptolepine, luteolin, and apigenin with AKT1 and HSP90AA1. VA provides both biochemical and mechanistic protection against ethanol-induced liver damage, highlighting its therapeutic potential in ALD management.

pharmacology and toxicology↗