HCV- and HBV-mediated liver cancer converge on similar transcriptomic landscapes and immune profiles.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide, and a large proportion of HCC is attributable to viral causes including hepatitis B (HBV) and C virus (HCV). The pathogenesis of viral-mediated HCC can differ between HBV and HCV, but it is unclear how much these differences influence the tumors final molecular and immune profiles. Additionally, there are known sex differences in the molecular etiology of HCC, but sex differences have not been explored in the context of viral-mediated HCC. To determine the extent to which the viral status and sex impact the molecular and immune profiles of HCC, we performed differential expression and immune cell deconvolution analyses. We identified a large number of differentially expressed genes unique to the HBV or HCV tumor:tumor-adjacent comparison. Pathway enrichment analyses demonstrated that the changes unique to the HCV tumor:tumor-adjacent tissue were predominated by changes in the immune pathways. Immune cell deconvolution demonstrated that HCV tumor-adjacent tissue had the largest immune cell infiltrate, with no difference in the immune profiles within HBV and HCV tumor samples. We subsequently segregated the differential expression analyses by sex, but demonstrated that the low number of female samples led to an overestimate of differentially expressed genes unique to male tumors. This limitation highlights the importance of additional sampling of female HCC tumors to allow for a more complete analysis of the sex differences in HCC. Overall, this work demonstrates the convergence of HBV- and HCV-mediated HCC on a similar transcriptomic landscape and immune profile despite differences in the surrounding tissue. Author SummaryHepatocellular carcinoma (HCC) is a significant worldwide health challenge. The majority of cases are attributable to infection with hepatitis B (HBV) or C (HCV). HBV and HCV differ in their methods of transmission and how they cause cancer. Despite these differences, most treatment guidelines are ambivalent to the underlying viral etiology of the tumor. In the age of personalized medicine, we sought to determine how similar or different HCC was when mediated by HBV or HCV. Additionally, since previous work has demonstrated biological differences in the tumors between males and females, we sought to characterize the sex differences within viral-mediated HCC. We found that, although there are several genes with differences in HBV- and HCV-mediated tumors, the tumors appear to be more biologically similar than the corresponding tumor-adjacent tissue. This suggests a convergence on common pathways toward cancers even when the starting point differs. The lower number of female samples inhibits a full understanding of the biological differences between HCC in males and females. This presents a critical need in the field to increase the sampling of female cancers to enable a full understanding of the sex differences in HCC.