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Researchers Shed Light on how Hepatitis B Virus Causes Liver Cancer


Hepatitis B virus (HBV) is more often integrated in liver tumor cells than normal liver tissue cells, and multiple integrations may be linked to more aggressive disease progression and poorer survival, researchers reported in the May 27, 2012 advance online edition of Nature Genetics.

Over years or decades, chronic HBV infection can lead to advanced liver disease including cirrhosis and hepatocellular carcinoma (HCC), a type of primary liver cancer. HBV -- like HIV -- integrates itself into host cell chromosomes. In doing so it can interfere with normal cell growth and trigger cancer, but this process is not well understood.

In order to study HBV integration in liver cancer genomes, Wing-Kin Sung from the University of Hong Kong and colleagues from Singapore, China, Denmark, and the U.S. performed massively parallel sequencing of 81 HBV-positive and 7 HBV-negative HCC tumors and adjacent normal tissue.

Below is an edited excerpt from a press release issued by Singapore's Agency for Science, Technology, and Research describing the study and its findings.

Genome Institute of Singapore Scientists, in Collaboration with the Industry, Unravel Mechanism that Causes Liver Cancer

May 28, 2012 -- Scientists at the Genome Institute of Singapore (GIS) have unraveled the mechanism that causes liver cancer (hepatocellular carcinoma, HCC), one of the most common solid tumors worldwide. This genome-wide research was done in collaboration with colleagues from the National University of Singapore (NUS), University of Hong Kong, Eli Lilly & Co. USA, Merck Research Laboratories USA, Pfizer Oncology USA and Beijing Genomics Institute China.

The discovery was published in the prestigious scientific journal, Nature Genetics, on 27 May 2012. The GIS is a research institute under the umbrella of the Agency for Science, Technology and Research (A*STAR).

One major cause of liver cancer, or HCC, is high exposure to the hepatitis B virus (HBV), resulting in the integration of HBV into the victim’s genes. Individuals who carry HBV have a greater than 100-fold increased relative risk of developing HCC, considered to be a serious global health problem by the World Health Organization (WHO).

Due to technology and sample limitations in the past, only restricted results were found. In this study, the scientists leveraged massively parallel sequencing technology to survey the HBV integrations in paired tumor and adjacent non-tumor tissues from 88 Chinese HCC patients.

Their analyses revealed that the incidences of HBV integrations were high -- 76 of the 88 patients had HBV integration. Specifically, they discovered that HBV will integrate into genes CCNE1, SENP5, and ROCK1, causing an increase in the expression levels of these genes, and subsequently enhancing the tumor growth. This discovery is in addition to the previously reported integration into the TERT and MLL4 genes.

The scientists also observed that HBV integration induced chromosome instability, resulting in the scrambling of the genome.

First author Dr. Ken Sung Wing Kin, Senior Group Leader of Computational and Systems Biology at the GIS, said: "Very importantly, we showed that HBV integration affects the patient’s overall survival. This work improves our understanding of HBV integration in HCC, which may lead us to develop better therapies for this highly malignant disease."

"A lot of researchers have tried to study the importance of HBV integration sites, but with limited success," said Prof. Stephen Tsui, Professor at the School of Biomedical Sciences and Director at the Centre for Microbial Genomics and Proteomics, the Chinese University of Hong Kong. "Thanks to the recent advance in sequencing technology and the continuing efforts of the team, I am so excited to see the light at the end of the tunnel finally. The findings in this article have important implications for the relationship between hepatitis B virus and hepatocellular carcinoma."

Acting Executive Director of GIS Prof. Ng Huck Hui remarked: "Computational biology is a critical part of post-genome research. Ken, a senior group leader at the GIS, has elegantly demonstrated the importance of informatics in deciphering the complex sequence datasets and discovered the sites which the hepatitis B virus invades the human genome."

The study was funded by the Asian Cancer Research Group (ACRG), a not-for-profit organization formed by Eli Lilly, Merck, and Pfizer.



W-K Sung,H Zheng, S Li, et al. Genome-wide Survey of HBV Integration in Hepatocellular Carcinoma. Nature Genetics. May 27, 2012 (Epub ahead of print).

Other Source

Agency for Science, Technology and Research.Genome Institute of Singapore Scientists, in Collaboration with the Industry, Unravel Mechanism that Causes Liver Cancer. Press release. May 28, 2012.