Transcriptional and epigenetic regulation of Ca<sup>2+</sup>-signaling genes in hepatitis B-derived hepatocellular carcinoma and their association with the cancer hallmarks

<h4>Motivation</h4>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.<h4>Results</h4>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 (<i>FBLN1</i>, <i>STC2</i>, <i>C1R</i>, and <i>F2RL2</i>) 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.<h4>Availability and implementation</h4>All data generated or analyzed during this study are included in this article.