May 29, 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 the 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
Due to technology and sample limitations in the past, only restricted results were
found. In this study, the scientists leveraged on massively parallel sequencing
technology to survey the HBV integrations on 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 the HBV will integrate into genes CCNE1, SENP5 and ROCK1, causing an increase in the expression levels in these genes, and subsequently enhancing the tumor growth.
This discovery is in addition to the previously reported integration into the TERT and
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
“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
from the end of the tunnel finally. The findings in this article have important
implications on the relationship between hepatitis B virus and hepatocellular
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.
2012 advance online issue of Nature Genetics under the title “Genome-wide survey
of recurrent HBV integration in hepatocellular carcinoma”.
, Hancheng Zheng5,16
, Shuyu Li
, Ronghua Chen7,16
, Xiao Liu5,16
, Nikki P Lee1
, Wah H Lee4
, Pramila N Ariyaratne4
, Fabianus H Mulawadi
, Kwong F Wong1,8–10
, Angela M Liu1,8–10
Ronnie T Poon1
, Sheung Tat Fan1
, Kwong L Chan1
, Zhuolin Gong5
, Yujie Hu5
, Guan Wang5
, Qinghui Zhang5
, Thomas D Barber
, Wen-Chi Chou6
, Ke Hao7
, Wei Zhou7
, Chunsheng Zhang7
, James Hardwick7,11
, Jiangchun Xu12
, Zhengyan Kan12
, Hongyue Dai
, Mao Mao11,12
, Jun Wang5,13,14
& John M Luk1,8–10,15
1. Department of Surgery, University of Hong Kong, Hong Kong.
2. School of Computing, National University of Singapore (NUS), Singapore.
3. NUS Graduate School for Integrative Sciences & Engineering, National University
of Singapore, Singapore.
4. Department of Computational & Systems Biology, Genome Institute of Singapore,
5. Beijing Genomics Institute, Shenzhen, China.
6. Eli Lilly & Co., Indianapolis, Indiana, USA.
7. Merck Research Laboratories, Boston, Massachusetts, USA.
8. Department of Pharmacology, NUS, Singapore.
9. Department of Surgery, NUS, Singapore.
10. Cancer Science Institute, NUS, Singapore.
11. Asian Cancer Research Group, Inc., Wilmington, Delaware, USA.
12. Pfizer Oncology, San Diego, California, USA.
13. Department of Biology, University of Copenhagen, Copenhagen, Denmark.
14. The Novo Nordisk Foundation Center for Basic Metabolic Research, University of
Copenhagen, Copenhagen, Denmark.
15. Present address: Department of Oncology, Roche R&D Center (China) Ltd.,
16. These authors contributed equally to this work.
Correspondence should be addressed to Wing-Kin Sung at firstname.lastname@example.org
Genome Institute of Singapore
Office of Corporate Communications
Tel: (65) 6808 8013
About the Genome Institute of Singapore (GIS)
The Genome Institute of Singapore (GIS) is an institute of the Agency for Science,
Technology and Research (A*STAR). It has a global vision that seeks to use
genomic sciences to improve public health and public prosperity. Established in 2001
as a centre for genomic discovery, the GIS will pursue the integration of technology,
genetics and biology towards the goal of individualized medicine.
The key research areas at the GIS include Systems Biology, Stem Cell &
Developmental Biology, Cancer Biology & Pharmacology, Human Genetics, Infectious Diseases, Genomic Technologies, and Computational & Mathematical Biology. The genomics infrastructure at the GIS is utilized to train new scientific
talent, to function as a bridge for academic and industrial research, and to explore
scientific questions of high impact. www.gis.a-star.edu.sg
About the Agency for Science, Technology and Research (A*STAR)
The Agency for Science, Technology and Research (A*STAR) is the lead agency for
fostering world-class scientific research and talent for a vibrant knowledge-based and
innovation-driven Singapore. A*STAR oversees 14 biomedical sciences and physical
sciences and engineering research institutes, and six consortia & centres, located in
Biopolis and Fusionopolis as well as their immediate vicinity.
A*STAR supports Singapore's key economic clusters by providing intellectual,
human and industrial capital to its partners in industry. It also supports extramural
research in the universities, and with other local and international partners. www.a-
The research findings described in the press release can be found in the 27 May