Abstract

Motivation Dysregulation of Ca2+-signaling genes has been shown in some types of cancer; however, it is virtually unknown in hepatitis B-derived hepatocellular carcinoma (HBV-HCC). Here, we evaluate the transcriptional and epigenetic regulation of Ca2+-signaling genes in HBV-HCC and whether their expression is associated with cancer hallmarks, and prognostic potential.Results We identified 432 differentially expressed Ca2+-signaling genes in HBV-HCC, including 134 that are specific to this condition, and were not found in non-HBV HCC. Fifty-three of these genes were associated with cancer hallmarks, of which 17 exhibited potential prognostic value by Cox multivariate analyses. We also provide new evidence for epigenetic regulation by post-transcriptional histone modifications and DNA methylation at the promoter of some of these genes. Finally, using Least Absolute Shrinkage and Selection Operator (LASSO) regression, we identified a four-gene prognostic signature (FBLN1, STC2, C1R, and F2RL2) that robustly stratified patient outcomes. This study presents the first integrative transcriptomic and epigenetic analysis of Ca2+-signaling genes in HBV-HCC, introducing a novel four-gene signature with prognostic potential. These findings highlight the relevance of a dysregulation of a subset of Ca2+-signaling genes as a distinctive feature of HBV-HCC.Availability and implementation All data generated or analyzed during this study are included in this article.