{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T20:18:31Z","timestamp":1788985111392,"version":"build-2803163510"},"reference-count":49,"publisher":"American Society of Clinical Oncology (ASCO)","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["J Clin Oncol"],"abstract":"\n PURPOSE<\/jats:title>\n Genetic classification may advance precision medicine in diffuse large B-cell lymphoma (DLBCL), but existing tools like LymphGen (LG) are limited by complexity and incomplete classification and do not incorporate nongenetic features that affect disease biology and therapeutic outcomes. To address these limitations, we developed LG-sig (LGsig), a gene expression\u2013based platform that classifies all DLBCLs and harmonizes both genetic and nongenetic dimensions of the disease.<\/jats:p>\n <\/jats:sec>\n \n METHODS<\/jats:title>\n \n LGsig was built on the distinct subtype-specific gene expression signature of each LG class using paired genomic and transcriptomic data (National Cancer Institute\/British Columbia Cancer Agency; N = 764). Model development was restricted to DLBCLs classified into\n MYD88<\/jats:italic>\n L265P<\/jats:sup>\n \u00a0and\u00a0\n CD79B<\/jats:italic>\n \u00a0mutations (MCD),\n BCL6<\/jats:italic>\n \u00a0translocation and\u00a0\n NOTCH2<\/jats:italic>\n \u00a0mutations (BN2),\n EZH2<\/jats:italic>\n \u00a0mutations and\u00a0\n BCL2<\/jats:italic>\n \u00a0translocation (EZB), or\n SGK1<\/jats:italic>\n \u00a0and\u00a0\n TET2<\/jats:italic>\n \u00a0mutations (ST2). Gene features were selected by differential gene expression, with 294 genes being optimal for classification using a nearest shrunken centroid classifier. LGsig classifications were designated as\n MCDsig<\/jats:italic>\n ,\n BN2sig<\/jats:italic>\n ,\n ST2sig<\/jats:italic>\n , and\n EZBsig<\/jats:italic>\n . The final model was applied to RNAseq from archival samples from the POLARIX trial (N = 678) to assess outcomes after polatuzumab vedotin-R-CHP (pola-R-CHP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for each LGsig subtype.\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n \n LGsig accurately identified LG subtypes using transcriptional data alone and extended assignments to all previously LG-unclassified cases. Importantly, LG-unclassified DLBCLs reassigned by LGsig mirrored the transcriptional and clinical features of their corresponding LG counterparts, supporting their reclassification. In addition, LGsig reassigned LG A53 DLBCLs, characterized by aneuploidy and\n TP53<\/jats:italic>\n alterations, into more biologically and therapeutically relevant LGsig clusters. Finally, LGsig improved the performance of LG as a biomarker in the POLARIX study, by identifying distinct DLBCL subtypes exhibiting a survival benefit with pola-R-CHP over R-CHOP in both LG-classified and LG-unclassified cases.\n <\/jats:p>\n <\/jats:sec>\n \n CONCLUSION<\/jats:title>\n LGsig expands molecular classification beyond current genetic classifiers in DLBCL by integrating both genetic and transcriptional dimensions of the disease to better inform subtype-specific therapeutic strategies.<\/jats:p>\n <\/jats:sec>","DOI":"10.1200\/jco-26-00451","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T19:59:07Z","timestamp":1788983947000},"update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":0,"title":["LymphGen-Sig: Integrating Genetic and Transcriptional States to Predict Therapeutic Response in Diffuse Large B-Cell Lymphoma"],"prefix":"10.1200","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2091-821X","authenticated-orcid":false,"given":"Sravya","family":"Tumuluru","sequence":"first","affiliation":[{"name":"Department of Medicine, Cornell University, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9739-0866","authenticated-orcid":false,"given":"Alan","family":"Cooper","sequence":"additional","affiliation":[{"name":"Yale University School of Medicine, New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanwen","family":"Jiang","sequence":"additional","affiliation":[{"name":"Genentech, Inc, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9036-9463","authenticated-orcid":false,"given":"Connie Lee","family":"Batlevi","sequence":"additional","affiliation":[{"name":"Genentech, Inc, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9807-1274","authenticated-orcid":false,"given":"Will","family":"Harris","sequence":"additional","affiliation":[{"name":"Genentech, Inc, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9541-8666","authenticated-orcid":false,"given":"Gilles","family":"Salles","sequence":"additional","affiliation":[{"name":"Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6952-6073","authenticated-orcid":false,"given":"Marek","family":"Trneny","sequence":"additional","affiliation":[{"name":"First Faculty of Medicine, Charles University, General Hospital, Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Lenz","sequence":"additional","affiliation":[{"name":"Department of Medicine, Hematology, Oncology, and Pneumology, University Hospital M\u00fcnster, M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franck","family":"Morschhauser","sequence":"additional","affiliation":[{"name":"Department of Hematology, Hospital Claude Huriez, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6804-7943","authenticated-orcid":false,"given":"Fabrice","family":"Jardin","sequence":"additional","affiliation":[{"name":"Department of Hematology, Centre Henri Becquerel, Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5539-1096","authenticated-orcid":false,"given":"Sandhya","family":"Balasubramanian","sequence":"additional","affiliation":[{"name":"Genentech, Inc, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4883-8921","authenticated-orcid":false,"given":"Matthew","family":"Sugidono","sequence":"additional","affiliation":[{"name":"Genentech, Inc, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9665-7415","authenticated-orcid":false,"given":"Alex F.","family":"Herrera","sequence":"additional","affiliation":[{"name":"Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2967-6448","authenticated-orcid":false,"given":"Justin","family":"Kline","sequence":"additional","affiliation":[{"name":"Department of Medicine, Section of Hematology\/Oncology, University of Chicago, Chicago, 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