Unveiling a Novel Mechanism of Oncovirus-Induced Carcinogenesis

ABSTRACT
Seven well-established oncoviruses collectively contribute to approximately 12% of all human cancers. Chronic
infection with the hepatitis B virus (HBV) alone is responsible for approximately 360,000 liver cancer cases per
year worldwide. Unlike human papillomavirus (HPV), which promotes tumorigenesis through the provision of E6
and E7 oncogenes, the mechanisms underlying HBV-driven carcinogenesis remain incompletely understood.
The integration of HBV sequences into the host genome is widely observed in HBV positive tumors, suggesting
its oncogenic role. It is hypothesized that HBV integrations may directly alter the protein sequence or expression
level of nearby genes and increase genome instability. We conducted long-read sequencing on HBV-positive
tumors and cell lines to fully map HBV integrations. Surprisingly, we identified HBV integration-bridged
chromosomal translocation events in all analyzed samples, indicating their frequent occurrence in HBV-
positive tumors. These chromosomal structural variations may facilitate enhancer hijacking, bringing strong
enhancers into proximity with oncogenes located in different chromosomes or topologically associating domains
(TADs). Enhancer hijacking has been widely implicated in human cancer, but has not been connected to
oncoviral integration. We propose that HBV integration-bridged chromosomal translocations lead to
enhancer hijacking, contributing to the tumorigenesis of HBV-positive tumors. To test this hypothesis, we
performed high-throughput chromosome conformation capture (HiC) on Tong and SNU761 cell lines to profile
genome-wide DNA-DNA interactions. Our analysis revealed neo-TADs across HBV integration-bridged
chromosomal translocations, affecting key cancer genes such as NRAS and ST3GAL1. In this study, we aim to
validate these enhancer-hijacking events (Aim 1) and identify additional events in other cell lines (Aim 2). Our
findings will unveil a novel mechanism of oncovirus-induced tumorigenesis. Furthermore, considering that agents
disrupting enhancer function, such as BET and CDK inhibitors, have shown promising results in clinical trials for
various cancers, our study may nominate these enhancer-targeting drugs for liver cancer treatment.

Grant Number: 1R03CA297201-01
NIH Institute/Center: NIH
Principal Investigator: Jian Cao