BGI, Asian Cancer Research Group publish genome-wide study of hep B virus
SHENZEN, China—BGI and the Asian Cancer Research Group have published the results of a whole genome-wide study of recurrent hepatitis B virus (HBV) integration in hepatocellular carcinoma (HCC). According to the authors of the study, which was published in Nature Genetics, their results provide important insights that may be used to improve diagnosis and treatment of HCC, the most common form of liver cancer worldwide.
"This study provided new insight into mechanisms of HBV integration, which promote liver cancer and affect clinical outcomes," said Dr. Ken Sung, lead author of the publication, National University of Singapore and honorary associate professor of Hong Kong University. "We expect further investigation may lead to improved diagnosis and treatment of HCC."
The collaborators carried out whole-genome sequencing in a large sample cohort of Chinese patients with HCC to characterize genome integration patterns and determine the prevalence of integrated HBV. Through the sequencing and analysis, researchers found that HBV integration was a common event in liver tumors and was observed more frequently in tumors (86.4 percent) than in adjacent normal liver tissues (30.7 percent). In addition to the previously reported TERT and MLL4 genes, researchers discovered three novel genes (CCNE1, SENP5 and ROCK1) associated with recurrent HBV integrations, each of which are known to play an important role in cancer development and progression.
Researchers also observed that the number of HBV integration events (recurrences) is positively associated with the tumor size, serum HBsAg and α-fetoprotein level. Patients with no or low numbers of detected HBV integrations in their tumor survived longer than those with a high number of HBV integrations, suggesting that HBV integration events are a negative prognostic indicator in HCC patients.
The researchers indicated that HBV integrations have some characteristics that may help the virus to control specific genes in the host tumor. They found HBV integration sites are typically found close to or inside of the targeted genes, which may be a mechanism for HBV to control the expression of some oncogenes or tumor suppressor genes. More than 40 percent of the integrations were observed to break the HBV genome at position 1,800 and integrate into the human genome. This may be due to the fact that the HBV enhancer and the HBV ORF replication sites are found at this locus. Moreover, they observed that HBV integrations correlated with increased DNA copy number around HBV integration breakpoints, which provides evidence that HBV integration initializes the chromosomal instability of the HCC genome.
"This study is of great interest to the scientific community, which is working toward better understanding HBV integration in HCC," said Hancheng Zheng, primary investigator of this project at BGI. "Based on these results, we can better explore the detailed molecular mechanism and clinical impact of HBV integration, promoting the discovery and development of future liver cancer treatments."