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dc.contributorVall d'Hebron Barcelona Hospital Campus
dc.contributor.authorvan Buuren, Nicholas
dc.contributor.authorRamirez, Ricardo
dc.contributor.authorSoulette, Cameron
dc.contributor.authorSuri, Vithika
dc.contributor.authorHan, Dong
dc.contributor.authorMay, Lindsey
dc.contributor.authorButi Ferret, Maria
dc.date.accessioned2022-08-10T06:26:01Z
dc.date.available2022-08-10T06:26:01Z
dc.date.issued2022-04-01
dc.identifier.citationvan Buuren N, Ramirez R, Soulette C, Suri V, Han D, May L, et al. Targeted long-read sequencing reveals clonally expanded HBV-associated chromosomal translocations in patients with chronic hepatitis B. JHEP Rep. 2022 Apr 1;4(4):100449.
dc.identifier.issn2589-5559
dc.identifier.urihttp://hdl.handle.net/11351/7974
dc.descriptionChronic HBV; Clonal expansion; Targeted sequencing
dc.description.abstractBackground & Aims HBV infects over 257 million people worldwide and is associated with the development of hepatocellular carcinoma (HCC). Integration of HBV DNA into the host genome is likely a key driver of HCC oncogenesis. Here, we utilise targeted long-read sequencing to determine the structure of HBV DNA integrations as well as full isoform information of HBV mRNA with more accurate quantification than traditional next generation sequencing platforms. Methods DNA and RNA were isolated from fresh frozen liver biopsies collected within the GS-US-174-0149 clinical trial. A pan-genotypic panel of biotinylated oligos was developed to enrich for HBV sequences from sheared genomic DNA (∼7 kb) and full-length cDNA libraries from poly-adenylated RNA. Samples were sequenced on the PacBio long-read platform and analysed using a custom bioinformatic pipeline. Results HBV-targeted long-read DNA sequencing generated high coverage data spanning entire integrations. Strikingly, in 13 of 42 samples (31%) we were able to detect HBV sequences flanked by 2 different chromosomes, indicating a chromosomal translocation associated with HBV integration. Chromosomal translocations were unique to each biopsy sample, suggesting that each originated randomly, and in some cases had evidence of clonal expansion. Using targeted long-read RNA sequencing, we determined that upwards of 95% of all HBV transcripts in patients who are HBeAg-positive originate from cccDNA. In contrast, patients who are HBeAg-negative expressed mostly HBsAg from integrations. Conclusions Targeted lso-Seq allowed for accurate quantitation of the HBV transcriptome and assignment of transcripts to either cccDNA or integration origins. The existence of multiple unique HBV-associated inter-chromosomal translocations in non-HCC CHB patient liver biopsies suggests a novel mechanism with mutagenic potential that may contribute to progression to HCC.
dc.language.isoeng
dc.publisherElsevier
dc.relation.ispartofseriesJHEP Reports;4(4)
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceScientia
dc.subjectHepatitis B - Aspectes genètics
dc.subjectTranscripció genètica
dc.subject.meshHepatitis B, Chronic
dc.subject.mesh/genetics
dc.subject.meshTranscription, Genetic
dc.titleTargeted long-read sequencing reveals clonally expanded HBV-associated chromosomal translocations in patients with chronic hepatitis B
dc.typeinfo:eu-repo/semantics/article
dc.identifier.doi10.1016/j.jhepr.2022.100449
dc.subject.decshepatitis B crónica
dc.subject.decs/genetica
dc.subject.decstranscripción genética
dc.relation.publishversionhttps://doi.org/10.1016/j.jhepr.2022.100449
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.audienceProfessionals
dc.contributor.organismesInstitut Català de la Salut
dc.contributor.authoraffiliation[van Buuren N, Ramirez R, Soulette C, Suri V, Han D, May L] Gilead Sciences Inc., Foster City, CA, USA. [Buti M] Vall d’Hebron Hospital Universitari, Barcelona, Spain
dc.identifier.pmid35295767
dc.identifier.wos000790250200007
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess


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