{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:53:49Z","timestamp":1785405229958,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,4]]},"group-title":"Cancer Biology","reference-count":87,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T00:00:00Z","timestamp":1775260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"National Cancer Institute","award":["PO1 CA022443"],"award-info":[{"award-number":["PO1 CA022443"]}]},{"name":"National Cancer Institute","award":["U01 CA275247"],"award-info":[{"award-number":["U01 CA275247"]}]},{"name":"National Cancer Institute","award":["R01 CA229673"],"award-info":[{"award-number":["R01 CA229673"]}]},{"award":["P30 CA014520"],"award-info":[{"award-number":["P30 CA014520"]}],"id":[{"id":"https:\/\/ror.org\/01e4byj08","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Diffuse large B-cell lymphoma (DLBCL), the most common aggressive lymphoma, encompasses histologically similar but genetically distinct cancers. Recent genetic studies have defined at least six molecular subtypes, yet none account for Epstein-Barr virus (EBV), despite 5-15% of DLBCLs being EBV-associated. By reanalyzing published whole-exome and RNA-sequencing data from 481 tumors, we identified 19 EBV-positive cases. These were significantly enriched in the BN2 subtype (6\/19), while most (11\/19) remained unclassified. In BN2 tumors, several subtype-defining mutations were reduced in frequency among EBV-positive cases, supporting the hypothesis that EBV oncogenes substitute for specific cellular alterations and may confound DLBCL classification algorithms. Extending our analysis to cell lines, we found that the widely used Val cell line harbors the B95-8 laboratory EBV strain; other EBV-positive lines appeared authentic but modeled only non-BN2 subtypes and expressed an atypical viral latency III program, whereas some DLBCL tumors expressed the atypical latency III program and others latency I or II. Together, these findings demonstrate that EBV-positive DLBCL, like DLBCL itself, is not a single disease, and that current\n                  <jats:italic>in vitro<\/jats:italic>\n                  models only partially capture its biological heterogeneity.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Key points<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>EBV-positive DLBCL is not a single disease and EBV status can impact genetic-based classifications.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Current EBV-positive DLBCL cell lines do not adequately capture tumor complexity; we determined that Val is a problematic cell line.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.03.710620","type":"posted-content","created":{"date-parts":[[2026,4,5]],"date-time":"2026-04-05T03:00:12Z","timestamp":1775358012000},"source":"Crossref","is-referenced-by-count":0,"title":["Integrating Epstein-Barr virus (EBV) status into diffuse large B cell lymphoma (DLBCL) genetics"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0394-1573","authenticated-orcid":false,"given":"Quincy","family":"Rosemarie","sequence":"first","affiliation":[{"name":"McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2736-6542","authenticated-orcid":false,"given":"Mitchell","family":"Hayes","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5741-9708","authenticated-orcid":false,"given":"Eric C","family":"Johannsen","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, United States of America"},{"name":"Department of Medicine, Infectious Disease Division, University of Wisconsin-Madison, Madison, Wisconsin, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026040708552479000_2026.04.03.710620v1.1","doi-asserted-by":"crossref","unstructured":"Miyazaki K . 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