Comparative transcriptomic analysis uncovers molecular heterogeneity in hepatobiliary cancers

Hepatobiliary cancers (HBCs) pose a major global health challenge, with a lack of effective targeted biomarkers. Due to their complex anatomical locations, shared risk factors, and the limitations of targeted therapies, generalized treatment strategies are often used for gallbladder cancer (GBC), hepatocellular carcinoma (HCC), and intrahepatic cholangiocarcinoma (ICC). This study aimed to identify specific transcriptomic signatures in GBC, HCC, and ICC. The transcriptomic data analysis revealed distinct expression profiles, highlighting complex molecular heterogeneity within these cancers, even within the same organ system. Functional annotation revealed distinct biological pathways associated with each type of HBCs. GBC was linked to cell cycle regulation, HCC was associated with immune system modulation, and ICC was involved in metabolic dysregulation, particularly lipid metabolism. Gene co-expression network (GCN) and protein-protein interaction (PPI) network analyses identified potential key genes, such as MAPK3 and ERBB2 in GBC, AC069287.1 and ACTN2 in HCC, and TRPC1 and BACE1 in ICC. The FOX family of transcription factors (TFs) was conserved across all three cancer types. To further explore the relationship between Epithelial-Mesenchymal Transition (EMT) and the identified hub genes and TFs, an EMT score analysis was conducted. This analysis revealed distinct phenotypic characteristics in each cancer type, with TFs identified in GBC and ICC showing a stronger correlation with EMT compared to those in HCC. External validation using The Cancer Genome Atlas (TCGA) databases confirmed the expression of candidate genes, underscoring their potential as therapeutic targets. These findings provide valuable insights into the molecular heterogeneity and complexity of HBCs, opening new avenues for personalized therapeutic interventions.