Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma.
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.
Department of Surgery, University of Hong Kong, Hong Kong, China.
Wing-Kin
WK
Sung
Hancheng
H
Zheng
Shuyu
S
Li
Ronghua
R
Chen
Xiao
X
Liu
Yingrui
Y
Li
Nikki P
NP
Lee
Wah H
WH
Lee
Pramila N
PN
Ariyaratne
Chandana
C
Tennakoon
Fabianus H
FH
Mulawadi
Kwong F
KF
Wong
Angela M
AM
Liu
Ronnie T
RT
Poon
Sheung Tat
ST
Fan
Kwong L
KL
Chan
Zhuolin
Z
Gong
Yujie
Y
Hu
Zhao
Z
Lin
Guan
G
Wang
Qinghui
Q
Zhang
Thomas D
TD
Barber
Wen-Chi
WC
Chou
Amit
A
Aggarwal
Ke
K
Hao
Wei
W
Zhou
Chunsheng
C
Zhang
James
J
Hardwick
Carolyn
C
Buser
Jiangchun
J
Xu
Zhengyan
Z
Kan
Hongyue
H
Dai
Mao
M
Mao
Christoph
C
Reinhard
Jun
J
Wang
John M
JM
Luk
D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000821:virology*; D043171:Chromosomal Instability / Q000235:genetics; D019927:Cyclin E / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006515:Hepatitis B virus / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000821:virology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D015996:Survival Rate; D019098:Telomerase / Q000235:genetics; D016662:Virus Integration / Q000235:genetics*
C475820:CCNE1 protein, human; D019927:Cyclin E; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D015513:Oncogene Proteins; D012367:RNA, Viral; D011495:Histone-Lysine N-Methyltransferase; C530816:MLL4 protein, human; C509186:TERT protein, human; D019098:Telomerase