Guta, Amerti

Abstract Background: Hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, develops through multiple pathways; however, the extent to which HBV, HCV, and non-viral etiologies shape tumor biology and influence treatment responses remain incompletely understood. The availability of viral detection methods from sequencing data and multiomics workflows give us a new opportunities to study how etiology influences the molecular landscape of HCC. Here, we analyze TCGA's LIHC samples categorized into HBV-, HCV-, and non-viral tumors to compare genomic, transcriptomic and methylation profile of these HCC tumors to identify biological pathways specific to each group. Methods: Whole-exome, RNA-seq, and clinical data from TCGA-LIHC (n=325) were analyzed. Viral status was assigned using Exogene (≥5 HBV/HCV reads; mixed infections excluded; non-viral = 0 reads). Mutation and clinical comparisons were performed using cBioPortal. RNA-seq data were processed with edgeR for 3-way differential expression (median count ≥25; |log2FC|>2; FDR<0.05). Pathway enrichment used ShinyGO. Findings were validated using the GSE62232 microarray cohort analyzed with limma. Results: Demographic patterns reflected known risk profiles: HBV patients presented younger (mean 53.9 years) and were predominantly male (78.8%) and Asian (92.9%), while HCV and non-viral groups were older and primarily White. Non-viral HCC showed the highest proportion of females (42.7%) and nearly half lacked significant fibrosis, consistent with metabolic disease. In contrast, HCV had the highest cirrhosis burden (47.2%), and HBV tumors showed the greatest proportion of poorly differentiated histology (52.2%).The comparison of the expressed genes between the 3 tumor subtypes revealed distinct etiology-associated pathways. Metabolic and mitochondrial including fatty acid β-oxidation differential expressed in Non-viral HCC. Activation of antiviral and interferon signaling, including type I IFN response and OAS-mediated defense pathways are observed in HCV-HCC. Finally, Cell-cycle and proliferation pathways are differentially expressed in HBV-positive, a finding consistent with effects of viral integration. Clustering analysis separated HBV and non-viral tumors into distinct groups. These signatures were reproduced in a validation cohort. Conclusion: Our analyses highlight that HBV-, HCV-, and non-viral HCC harbor distinct transcriptional and signaling pathways. These etiology-specific signatures provide a framework for developing more precise biomarkers and for tailoring therapeutic strategies to the molecular biology of each etiology. Acknowledgement: We acknowledge the late Dr. Sean Cleary, MD, for his invaluable contributions to this project. Disclosure: AI has been used to trim sentences in order to fit in the word limit. Citation Format: Amerti Guta, Daniel O'Brien, Aditya V. Bhagwate, Jean-Pierre A. Kocher, Lewis R. Roberts. Multiomic dissection of HBV-, HCV-, and non-viral HCC reveals distinct proliferation, interferon, and metabolic signatures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2682.

Biliary tract cancers, including cholangiocarcinoma, gallbladder, and ampulla of Vater cancers, rank second among hepatobiliary cancers, known for their poor prognoses. The United States has witnessed a notable increase in intrahepatic cholangiocarcinoma incidence. This study examines the incidence and survival outcomes of biliary tract cancers in Olmsted County, Minnesota from 1976 to 2018. Using data from the Rochester Epidemiology Project (REP), residents aged 20 and above were analyzed across four eras. Incidence rates were calculated and adjusted for age and sex, and temporal trends were assessed using Poisson regression. Intrahepatic cholangiocarcinoma exhibited a significant escalation in incidence rates over time, while gallbladder cancers showed a decline among women. Median survival times for biliary tract cancers notably improved. These findings confirm the rising incidence of intrahepatic cholangiocarcinoma and suggest improving survival rates. Nevertheless, the overall prognosis for biliary tract cancers remains very poor, emphasizing the continual need for enhanced management strategies and further research.