title: Recurrent targeted genes of hepatitis B virus in the liver cancer genomes identified by a next-generation sequencing-based approach.
abstract: Integration of the viral DNA into host chromosomes was found in most of the hepatitis B virus (HBV)-related hepatocellular carcinomas (HCCs). Here we devised a massive anchored parallel sequencing (MAPS) method using next-generation sequencing to isolate and sequence HBV integrants. Applying MAPS to 40 pairs of HBV-related HCC tissues (cancer and adjacent tissues), we identified 296 HBV integration events corresponding to 286 unique integration sites (UISs) with precise HBV-Human DNA junctions. HBV integration favored chromosome 17 and preferentially integrated into human transcript units. HBV targeted genes were enriched in GO terms: cAMP metabolic processes, T cell differentiation and activation, TGF beta receptor pathway, ncRNA catabolic process, and dsRNA fragmentation and cellular response to dsRNA. The HBV targeted genes include 7 genes (PTPRJ, CNTN6, IL12B, MYOM1, FNDC3B, LRFN2, FN1) containing IPR003961 (Fibronectin, type III domain), 7 genes (NRG3, MASP2, NELL1, LRP1B, ADAM21, NRXN1, FN1) containing IPR013032 (EGF-like region, conserved site), and three genes (PDE7A, PDE4B, PDE11A) containing IPR002073 (3', 5'-cyclic-nucleotide phosphodiesterase). Enriched pathways include hsa04512 (ECM-receptor interaction), hsa04510 (Focal adhesion), and hsa04012 (ErbB signaling pathway). Fewer integration events were found in cancers compared to cancer-adjacent tissues, suggesting a clonal expansion model in HCC development. Finally, we identified 8 genes that were recurrent target genes by HBV integration including fibronectin 1 (FN1) and telomerase reverse transcriptase (TERT1), two known recurrent target genes, and additional novel target genes such as SMAD family member 5 (SMAD5), phosphatase and actin regulator 4 (PHACTR4), and RNA binding protein fox-1 homolog (C. elegans) 1 (RBFOX1). Integrating analysis with recently published whole-genome sequencing analysis, we identified 14 additional recurrent HBV target genes, greatly expanding the HBV recurrent target list. This global survey of HBV integration events, together with recently published whole-genome sequencing analyses, furthered our understanding of the HBV-related HCC.
authors.affiliation: Hangzhou Proprium Biotech, Hangzhou, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Ding
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Lou
authors.forename: Dasong
authors.initials: D
authors.lastname: Hua
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.forename: Lisha
authors.initials: L
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Na
authors.initials: N
authors.lastname: Zhao
authors.forename: Guoping
authors.initials: G
authors.lastname: Ren
authors.forename: Lanjuan
authors.initials: L
authors.lastname: Li
authors.forename: Biaoyang
authors.initials: B
authors.lastname: Lin
mesh_terms: D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000821:virology*; D002454:Cell Differentiation; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics / Q000302:isolation & purification; D015894:Genome, Human; D006515:Hepatitis B virus / Q000235:genetics / Q000302:isolation & purification; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000821:virology; D019098:Telomerase / Q000235:genetics; D016662:Virus Integration
chemical_list: D004279:DNA, Viral; D019098:Telomerase