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Oncol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL) are aggressive histological subtypes of non-Hodgkin\u2019s lymphoma. Improved understanding of the underlying molecular pathogenesis has led to new classification and risk stratification tools, including the development of cell-free biomarkers through liquid biopsies. The goal of this study was to investigate cell-free RNA (cfRNA) biomarkers in DLBCL and PMBCL patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>Blood plasma samples (n=168) and matched diagnostic formalin-fixed paraffin-embedded (FFPE) tissue samples (n=69) of DLBCL patients, PMBCL patients and healthy controls were collected between 2016-2021. Plasma samples were collected at diagnosis, at interim evaluation, after treatment, and in case of refractory or relapsed disease. RNA was extracted from 200 \u00b5l plasma using the miRNeasy serum\/plasma kit and from FFPE tissue using the miRNeasy FFPE kit. RNA was subsequently sequenced on a NovaSeq 6000 instrument using the SMARTer Stranded Total RNA-seq pico v3 library preparation kit.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Higher cfRNA concentrations were demonstrated in lymphoma patients compared to healthy controls. A large number of differentially abundant genes were identified between the cell-free transcriptomes of DLBCL patients, PMBCL patients, and healthy controls. Overlap analyses with matched FFPE samples showed that blood plasma has a unique transcriptomic profile that significantly differs from that of the tumor tissue. As a good concordance between tissue-derived gene expression and the immunohistochemistry Hans algorithm for cell-of-origin (COO) classification was demonstrated in the FFPE samples, but not in the plasma samples, a 64-gene cfRNA classifier was developed that can accurately determine COO in plasma. High plasma levels of a 9-gene signature (<jats:italic>BECN1<\/jats:italic>, <jats:italic>PRKCB<\/jats:italic>, <jats:italic>COPA<\/jats:italic>, <jats:italic>TSC22D3<\/jats:italic>, <jats:italic>MAP2K3<\/jats:italic>, <jats:italic>UQCRHL<\/jats:italic>, <jats:italic>PTMAP4<\/jats:italic>, <jats:italic>EHD1<\/jats:italic>, <jats:italic>NAP1L1<\/jats:italic> pseudogene) and a 5-gene signature (<jats:italic>FTH1P7<\/jats:italic>, <jats:italic>PTMAP4<\/jats:italic>, <jats:italic>ATF4<\/jats:italic>, <jats:italic>FTH1P8<\/jats:italic>, <jats:italic>ARMC7<\/jats:italic>) were significantly associated with inferior progression-free and overall survival in DLBCL patients, respectively, independent of the NCCN-IPI score.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Total RNA sequencing of blood plasma samples allows the analysis of the cell-free transcriptome in DLBCL and PMBCL patients and demonstrates its unexplored potential in identifying diagnostic, cell-of-origin, and prognostic cfRNA biomarkers.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2023.1221471","type":"journal-article","created":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T10:45:17Z","timestamp":1698230717000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Exploring the cell-free total RNA transcriptome in diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma patients as biomarker source in blood plasma liquid biopsies"],"prefix":"10.3389","volume":"13","author":[{"given":"Philippe","family":"Decruyenaere","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Giuili","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Verniers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasper","family":"Anckaert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrien","family":"De Grove","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mala\u00efka","family":"Van der Linden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dries","family":"Deeren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo","family":"Van Dorpe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fritz","family":"Offner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo","family":"Vandesompele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,10,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-01-643569","article-title":"The 2016 revision of the World Health Organization classification of lymphoid neoplasms","volume":"127","author":"Swerdlow","year":"2016","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-03-769620","article-title":"Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study","volume":"130","author":"Crump","year":"2017","journal-title":"Blood"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/35000501","article-title":"Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling","volume":"403","author":"Alizadeh","year":"2000","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-05-1545","article-title":"Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray","volume":"103","author":"Hans","year":"2004","journal-title":"Blood"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-06-1841","article-title":"The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma","volume":"102","author":"Savage","year":"2003","journal-title":"Blood"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20031074","article-title":"Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma","volume":"198","author":"Rosenwald","year":"2003","journal-title":"J Exp Med"},{"key":"B7","volume-title":"Primary mediastinal (thymic) large B-cell lymphoma. 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