Recurrent HBV Integration Targets as Potential Drivers in Hepatocellular Carcinoma

Abstract

Chronic hepatitis B virus (HBV) infection is the major etiology of hepatocellular carcinoma (HCC), frequently with HBV integrating into the host genome. HBV integration, found in 85% of HBV-associated HCC (HBV–HCC) tissue samples, has been suggested to be oncogenic. Here, we investigated the potential of HBV–HCC driver identification via the characterization of recurrently targeted genes (RTGs). A total of 18,596 HBV integration sites from our in-house study and others were analyzed. RTGs were identified by applying three criteria: at least two HCC subjects, reported by at least two studies, and the number of reporting studies. A total of 396 RTGs were identified. Among the 28 most frequent RTGs, defined as affected in at least 10 HCC patients, 23 (82%) were associated with carcinogenesis and 5 (18%) had no known function. Available breakpoint positions from the three most frequent RTGs, TERT, MLL4/KMT2B, and PLEKHG4B, were analyzed. Mutual exclusivity of TERT promoter mutation and HBV integration into TERT was observed. We present an RTG consensus through comprehensive analysis to enable the potential identification and discovery of HCC drivers for drug development and disease management.

Potential multi-modal effects of provirus integration on HIV-1 persistence: lessons from other viruses

“…HBV and HPV integrations have been shown to directly target genes that control various cellular functions other than proliferation, including survival, and can ward off CTL through overexpression of inhibitory ligands [34,35,[65][66][67] (Box 3). Some of these HPV findings are recent and were enabled by technological advances that shed new light on proviral integration landscapes.…”

“…Integrations of HPV and HBV sequences can induce the expression of prosurvival factors. For HBV, the RIG FOXP2 [66,67] encodes a transcription factor that contributes to preventing inflammation and apoptosis [94]. Similarly, primary oropharyngeal cancer cells show an HPV integration hotspot in intron 10 of BRISC and BRCA1 A complex member 2 (BABAM2) [35], a gene that blocks TNF-α-induced apoptosis [95].…”

“…Viruses for which experimental evidence exists for integration and transcriptional upregulation of genes involved in the indicated cellular functions are listed above each cellular mechanism. HBV, HPV, and Epstein-Barr virus (EBV) integration can upregulate the expression of antiapoptotic proteins [34,35,[65][66][67]. HBV integration can result in upregulation of FOXP2, a gene that encodes a transcription factor with antiapoptotic functions [66,67].…”

“…HBV, HPV, and Epstein-Barr virus (EBV) integration can upregulate the expression of antiapoptotic proteins [34,35,[65][66][67]. HBV integration can result in upregulation of FOXP2, a gene that encodes a transcription factor with antiapoptotic functions [66,67]. Antiapoptotic genes targeted by HPV include ETS2 [34] and BABAM2 [35], a gene that encodes an antiapoptotic protein that blocks tumor necrosis factor alpha (TNF-α)-induced apoptosis [95].…”

HBx and YAP expression could promote tumor development and progression in HBV-related hepatocellular carcinoma

“…These features are related to various factors including chronic inflammation, the integration of HBV-DNA into the host hepatocyte genomic DNA, and the expression of viral proteins, which transactivate human oncogenes [ [6] , [7] , [8] , [9] ]. The molecular mechanisms of HBV-related HCC occurrence include the contribution of hepatitis B virus X (HBx) protein, which consists of 154 amino acids and is essential for the effective replication of HBV.…”