Genome Institute of Singapore Scientists, in Collaboration With the Industry, Unravels Mechanism That Causes Liver Cancer

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 Organization (WHO).

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 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 from the end of the tunnel finally. The findings in this article have important implications on 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.

Research publication:

2012 advance online issue of Nature Genetics under the title “Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma”.

Authors:

Wing-Kin Sung1–4,16 , Hancheng Zheng5,16 , Shuyu Li

6,16 , Ronghua Chen7,16 , Xiao Liu5,16 , Yingrui Li

5 , Nikki P Lee1 , Wah H Lee4 , Pramila N Ariyaratne4 , Chandana Tennakoon2,3 , Fabianus H Mulawadi

4 , Kwong F Wong1,8–10 , Angela M Liu1,8–10 , Ronnie T Poon1 , Sheung Tat Fan1 , Kwong L Chan1 , Zhuolin Gong5 , Yujie Hu5 , Zhao Lin

5 , Guan Wang5 , Qinghui Zhang5 , Thomas D Barber

6 , Wen-Chi Chou6 , Amit Aggarwal 6 , Ke Hao7 , Wei Zhou7 , Chunsheng Zhang7 , James Hardwick7,11 , Carolyn Buser

7 , Jiangchun Xu12 , Zhengyan Kan12 , Hongyue Dai

7 , Mao Mao11,12 , Christoph Reinhard6 , 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, 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., Shanghai, China.

16. These authors contributed equally to this work.

Correspondence should be addressed to Wing-Kin Sung at sungk@gis.a-star.edu.sg

Contact

Winnie Lim

Genome Institute of Singapore

Office of Corporate Communications

Tel: (65) 6808 8013

Email: limcp2@gis.a-star.edu.sg

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- star.edu.sg

The research findings described in the press release can be found in the 27 May