Recurrent Targeted Genes of Hepatitis B Virus in the Liver Cancer Genomes Identified by a Next-Generation Sequencing-Based Approach

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. © 2012 ding et al.