Journal Article

Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma

Dai, Hongyue, Mulawadi, Fabianus H, Zhang, Chunsheng, Sung, Wing-Kin, Chan, Kwong L, Liu, Xiao, Lee, Wah H, Xu, Jiangchun, Wang, Guan, Hao, Ke, Zheng, Hancheng, Li, Shuyu, Lee, Nikki P, Ariyaratne, Pramila N, Poon, Ronnie T, Wong, Kwong F, Hardwick, James, Zhang, Qinghui, Chou, Wen-Chi, Aggarwal, Amit, Zhou, Wei, Kan, Zhengyan, Wang, Jun, Liu, Angela M, Li, Yingrui, Barber, Thomas D, Mao, Mao, Reinhard, Christoph, Luk, John M, Gong, Zhuolin, Chen, Ronghua, Tennakoon, Chandana, Buser, Carolyn, Hu, Yujie, Fan, Sheung Tat, Lin, Zhao

2012

Overview

John Luk and colleagues report the sequencing of 81 hepatitis B virus (HBV)-positive and 7 HBV-negative hepatocellular carcinomas and matched normal tissues. They confirm recurrent integration events of HBV at TERT and MLL4 and report recurrent events at the CCNE1 gene. To survey hepatitis B virus (HBV) integration in liver cancer genomes, we conducted massively parallel sequencing of 81 HBV-positive and 7 HBV-negative hepatocellular carcinomas (HCCs) and adjacent normal tissues. We found that HBV integration is observed more frequently in the tumors (86.4%) than in adjacent liver tissues (30.7%). Copy-number variations (CNVs) were significantly increased at HBV breakpoint locations where chromosomal instability was likely induced. Approximately 40% of HBV breakpoints within the HBV genome were located within a 1,800-bp region where the viral enhancer, X gene and core gene are located. We also identified recurrent HBV integration events (in ≥4 HCCs) that were validated by RNA sequencing (RNA-seq) and Sanger sequencing at the known and putative cancer-related TERT , MLL4 and CCNE1 genes, which showed upregulated gene expression in tumor versus normal tissue. We also report evidence that suggests that the number of HBV integrations is associated with patient survival.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/69 / 631/326/596/1550 / 692/699/67/1504/1610 / Agriculture / Animal Genetics and Genomics / Base Sequence / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - virology / Causes of / Chromosomal Instability - genetics / Cyclin E - genetics / DNA Copy Number Variations - genetics / DNA, Viral - genetics / DNA-Binding Proteins - genetics / Female / Fundamental and applied biological sciences. Psychology / Gastroenterology. Liver. Pancreas. Abdomen / Gene expression / Gene Function / Genetic aspects / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Genomes / Health aspects / Hepatitis B virus / Hepatitis B virus - genetics / Hepatoma / Human Genetics / Humans / letter / Liver cancer / Liver Neoplasms - genetics / Liver Neoplasms - virology / Liver. Biliary tract. Portal circulation. Exocrine pancreas / Male / Medical sciences / Middle Aged / Molecular Sequence Data / Oncogene Proteins - genetics / RNA, Viral - genetics / Studies / Survival Rate / Telomerase - genetics / Tumors / Virus Integration - genetics