Molecular Signature and Mechanisms of Hepatitis D Virus–Associated Hepatocellular Carcinoma

Abstract

There is limited data on the molecular mechanisms whereby hepatitis D virus (HDV) promotes liver cancer. Therefore, serum and liver specimens obtained at the time of liver transplantation from well-characterized patients with HDV-HCC ( = 5) and with non-HCC HDV cirrhosis ( = 7) were studied using an integrated genomic approach. Transcriptomic profiling was performed using laser capture-microdissected (LCM) malignant and nonmalignant hepatocytes, tumorous and nontumorous liver tissue from patients with HDV-HCC, and liver tissue from patients with non-HCC HDV cirrhosis. HDV-HCC was also compared with hepatitis B virus (HBV) HBV-HCC alone, and hepatitis C virus (HCV) HCV-HCC. HDV malignant hepatocytes were characterized by an enrichment of upregulated transcripts associated with pathways involved in cell-cycle/DNA replication, damage, and repair (Sonic Hedgehog, GADD45, DNA-damage-induced 14-3-3σ, cyclins and cell-cycle regulation, cell cycle: G-M DNA-damage checkpoint regulation, and hereditary breast cancer). Moreover, a large network of genes identified functionally relate to DNA repair, cell cycle, mitotic apparatus, and cell division, including 4 cancer testis antigen genes, attesting to the critical role of genetic instability in this tumor. Besides being overexpressed, these genes were also strongly coregulated. Gene coregulation was high not only when compared with nonmalignant hepatocytes, but also to malignant hepatocytes from HBV-HCC alone or HCV-HCC. Activation and coregulation of genes critically associated with DNA replication, damage, and repair point to genetic instability as an important mechanism of HDV hepatocarcinogenesis. This specific HDV-HCC trait emerged also from the comparison of the molecular pathways identified for each hepatitis virus-associated HCC. Despite the dependence of HDV on HBV, these findings suggest that HDV and HBV promote carcinogenesis by distinct molecular mechanisms. This study identifies a molecular signature of HDV-associated hepatocellular carcinoma and suggests the potential for new biomarkers for early diagnostics. .

Clinical outcomes in patients with hepatitis D, cirrhosis and persistent hepatitis B virus replication, and receiving long‐term tenofovir or entecavir

“…However, plasma levels of HDV‐RNA may fluctuate over time spontaneously, making it difficult to assess the association with disease outcome. Multiple molecular mechanisms are involved in the pathogenesis of HDV induced liver disease and cancer, which include imbalance in some genes activation in tumour tissue, activation of oxidative and DNA methylation pathways and possibly HBV genome deletions …”

Identification of Platform-Independent Diagnostic Biomarker Panel for Hepatocellular Carcinoma Using Large-Scale Transcriptomics Data

“…In this study, we extract raw expression data of 30 datasets, where 29 transcriptome datasets were obtained from GEO and one is from TCGA; each dataset contains at least 10 samples. The following is the list of datasets obtained from GEO: GSE102079 (Chiyonobu et al, 2018), GSE22405, GSE98383 (Diaz et al, 2018), GSE84402 (Wang et al, 2017), GSE64041 (Makowska et al, 2016), GSE69715 (Sekhar et al, 2018), GSE51401, GSE62232 (Schulze et al, 2015), GSE45267 (Chen et al, 2018a), GSE32879 (Oishi et al, 2012), GSE19665 (Deng et al, 2010), GSE107170 (Diaz et al, 2018), GSE76427 (Grinchuk et al, 2018), GSE39791 (Kim et al, 2014), GSE57957 (Mah et al, 2014), GSE87630 (Woo et al, 2017), GSE46408, GSE57555 (Murakami et al, 2015), GSE54236 (Villa et al, 2016;Zubiete-Franco et al, 2019), GSE65484 (Dong et al, 2015), GSE31370 (Seok et al, 2012), GSE84598, GSE89377, GSE29721 (Stefanska et al, 2011), GSE14323 (Mas et al, 2009), GSE25097 (Lamb et al, 2011;Tung et al, 2011;Wong et al, 2016), GSE14520 (Roessler et al, 2010;Zhao et al, 2015), GSE36376 (Lim et al, 2013), GSE36076). All GEO datasets were obtained using GEOquery package of Bioconductor in R-3.5.3.…”

Reply to: “Cirrhotic controls in a pooled analysis of hepatitis D and hepatocellular carcinoma”

“…2,3 That said, the fact that HDV does not integrate into the host cell genome does not exclude its direct oncogenic potential and experimental data indeed support a potential hepatocarcinogenic role of HDV antigens and a specific molecular signature of HDV-associated HCC. 4,5 The demonstration of a potential specific oncogenic role of HDV in human infection is only possible using robust cohort study designs where cirrhosis is no longer a confounder. In our analysis, only 1 cohort study accounted for cirrhosis as a confounder and found a significant hazard ratio of 2.1 for HCC in HDV-infected patients, independently of cirrhosis (which, nonsurprisingly, was itself found to be associated with HCC development).…”