Comparative transcriptomic analysis of hepatocellular carcinoma according to primary liver disease using TCGA-LIHC data

Abstract

Background and aim: Hepatocellular carcinoma arises in heterogeneous chronic liver conditions, including hepatitis B virus and hepatitis C virus infection, alcohol-associated liver disease, cirrhosis, and hepatic steatosis. The extent to which the tumor transcriptome reflects the underlying liver disease remains incompletely defined.

Methods: We analyzed publicly available data from The Cancer Genome Atlas Liver Hepatocellular

Carcinoma cohort by clinical background, comparing hepatitis C virus-associated and hepatitis B virus-associated tumors with their respective adjacent non-tumor tissue, viral hepatitis-associated with alcohol-associated tumors, and tumors arising with viral hepatitis, alcohol use, or cirrhosis versus steatosis-associated tumors. Differential expression was assessed using an unpaired t-test with Benjamini-Hochberg correction and a fold-change threshold of 1.5.

Results: Hepatitis C virus-associated tumors showed 451 differentially expressed genes versus adjacent non-tumor tissue (61 upregulated, 390 downregulated); hepatitis B virus-associated tumors showed 500 (143 upregulated, 357 downregulated). Of these, 269 were shared and all were concordantly regulated, the most strongly downregulated corresponding to liver sinusoidal endothelial cell markers. Viral hepatitis-associated and alcohol-associated tumors differed by only three genes. Comparisons involving steatosis-associated tumors revealed broader differences (107 to 233 genes) dominated by cytochrome P450, drug, and retinol metabolism; however, that subgroup comprised only 12 tumors, and these findings are exploratory. Ten differentially expressed non-coding transcripts, comprising nine long non-coding ribonucleic acids and one pseudogene, were shared between the hepatitis B virus and hepatitis C virus comparisons. By contrast, the non-coding transcripts shared across the steatosis comparisons were sex-chromosome-linked, could not be distinguished from an effect of sex composition, and were not interpreted further.

Conclusion: Hepatitis B virus-associated and hepatitis C virus-associated tumors therefore share a substantial, concordant transcriptional program despite differing viral etiologies, whereas differences associated with the underlying liver disease are concentrated in hepatic metabolic and xenobiotic-processing