Genomic Correlates of APOBEC-Associated Mutagenesis in Esophageal Squamous Cell Carcinoma
- 1University of Cape Coast
Abstract
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.
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BibTeX
@misc{ansah2026genomic,
title = {{Genomic Correlates of APOBEC-Associated Mutagenesis in Esophageal Squamous Cell Carcinoma}},
author = {E. O. Ansah and J. A. Yentumi and E. Y. Kodom and P. O. Mensah and K. Fosu and I. K. Adu and E. A. Boahen},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.27.762354},
url = {https://www.biorxiv.org/content/10.64898/2026.10.27.762354v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Genomic Correlates of APOBEC-Associated Mutagenesis in Esophageal Squamous Cell Carcinoma
AU - E. O. Ansah
AU - J. A. Yentumi
AU - E. Y. Kodom
AU - P. O. Mensah
AU - K. Fosu
AU - I. K. Adu
AU - E. A. Boahen
PY - 2026
DA - 2026/10/27
PB - bioRxiv
DO - 10.64898/2026.10.27.762354
UR - https://www.biorxiv.org/content/10.64898/2026.10.27.762354v1
AB - 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.
ER -