May 29, 2012, Shenzhen, China – The Asian Cancer Research Group (ACRG)—an independent, not-for-profit company established by Eli Lilly and Company, Merck (known as MSD outside the United States and Canada) and Pfizer Inc.—in collaboration with BGI—the world's largest genomics organization—today announced the publication of results from a whole genome-wide study of recurrent hepatitis B virus (HBV) integration in hepatocellular carcinoma (HCC) in Nature Genetics. Results from this first-of-its-kind study 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 (NUS) and Honorary Associate Professor of Hong Kong University (HKU). "We expect further investigation may lead to improved diagnosis and treatment of HCC."
HBV integration is thought to be one of the major causes of HCC and research has shown that the DNA of HBV could integrate into a host genome in such a manner as to induce chromosomal instability (a defining characteristic of most human cancers) or alter expression and function of endogenous genes. Previous studies of HBV integration into the HCC genome have been limited by technological hurdles and relatively small sample sizes.
In this study, ACRG, BGI and other 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.
"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."
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 (n<3) of detected HBV integrations in their tumor survived longer than those with a high number of HBV integrations (n>3), suggesting that HBV integration events are a negative prognostic indicator in HCC patients.
"A deep understanding of the recurring HBV insertions in HCC will help the research community identify novel molecular targets in liver cancer, for which effective treatments are still limited," said John Luk, Honorary Professor of HKU, Adjunct Professor of NUS and IMCB, Head of Oncology, Roche Shanghai.
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.
"Molecular characterization of these tumors in a relatively large patient population ultimately provides the basis for more targeted and effective medicines, and will lead to improved outcomes for liver cancer patients," said Christoph Reinhard, Ph.D., Director of the Board of ACRG, and Senior Director, Oncology Translational Science, Eli Lilly and Company. "The ACRG was established to fuel research directed towards improving our understanding of cancers affecting Asian populations. This study underscores that in a short period of time, by working together, we are able to generate important evidence that can be further investigated in the fight against liver cancer."
Source: BGI Shenzhen