{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T15:13:51Z","timestamp":1784042031886,"version":"3.55.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1008699","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T00:00:00Z","timestamp":1614297600000}}],"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,9]],"date-time":"2021-02-09T00:00:00Z","timestamp":1612828800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Hepatitis B virus (HBV) infection contributes to hepatocellular carcinoma (HCC) initiation and is associated with worse outcomes. Many prior studies of HBV-related HCC have not accounted for potential heterogeneity among HBV-related tumors by assessing whether HBV activity is present in tumor tissue. Here, we measured tumor HBV RNA, a proxy for viral activity, and investigated the association between HBV RNA status and several clinicogenomic characteristics. We obtained clinical, mutation, RNA-Seq and survival data for 439 HCC tumors from The Cancer Genome Atlas and International Cancer Genome Consortium. Tumors were classified as HBV RNA positive if they harbored &gt;1 HBV RNA read per million human reads. We investigated the association between HBV RNA status and nonsynonymous somatic mutations, gene set expression, homologous recombination deficiency (HRD) score and mutation-specific survival. HBV RNA positive status was associated with higher nonsynonymous mutation rates of multiple genes, including<jats:italic>TP53<\/jats:italic>and<jats:italic>CDKN2A<\/jats:italic>, while HBV RNA negative status was associated with higher nonsynonymous<jats:italic>BAP1<\/jats:italic>mutation rate. HBV RNA positive status was also associated with increased transcription of genes involved in multiple DNA damage repair pathways, genes upregulated by<jats:italic>MYC<\/jats:italic>and mTORC1, and genes overexpressed in several HCC subclasses associated with a proliferative phenotype. Further, HBV RNA positive status was associated with increased three-biomarker HRD score (22.2 for HBV RNA+ vs. 16.0 for HBV RNA-). Finally, HBV RNA status was associated with multiple mutation-specific survival differences, including decreased survival for HBV RNA positive patients with nonsynonymous<jats:italic>KEAP1<\/jats:italic>mutations compared to those without (hazard ratio 4.26). HCC tumors harboring genomic evidence of HBV activity therefore constitute a distinct HCC subset characterized by specific differences in nonsynonymous mutations, gene set expression, three-biomarker HRD score and mutation-specific survival.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1008699","type":"journal-article","created":{"date-parts":[[2021,2,10]],"date-time":"2021-02-10T02:20:55Z","timestamp":1612923655000},"page":"e1008699","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Tumor hepatitis B virus RNA identifies a clinically and molecularly distinct subset of hepatocellular carcinoma"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8161-1847","authenticated-orcid":true,"given":"Huat Chye","family":"Lim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8997-5725","authenticated-orcid":true,"given":"John D.","family":"Gordan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,2,9]]},"reference":[{"key":"pcbi.1008699.ref001","unstructured":"Cancer Today. 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