{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T15:00:13Z","timestamp":1768402813505,"version":"3.49.0"},"reference-count":28,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,18]],"date-time":"2021-12-18T00:00:00Z","timestamp":1639785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Portuguese Oncology Institute of Porto","award":["PI 27\u2013FB-CBEG-CI-IPOP"],"award-info":[{"award-number":["PI 27\u2013FB-CBEG-CI-IPOP"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","award":["SFRH\/BD\/132751\/2017"],"award-info":[{"award-number":["SFRH\/BD\/132751\/2017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Background: DLBCL represent a heterogeneous group of aggressive diseases. High grade B-cell lymphomas (HGBCL) were recently individualized from DLBCL as a discrete diagnostic entity due to their worse prognosis. Currently, although most patients are successfully treated with RCHOP regimens, 1\/3 will either not respond or ultimately relapse. Alterations in histone modifying enzymes have emerged as the most common alterations in DLBCL, but their role as prognostic biomarkers is controversial. We aimed to ascertain the prognostic value of EZH2 immunoexpression in RCHOP-treated DLBCL and HGBCL. Results: We performed a retrospective cohort study including 125 patients with RCHOP-treated DLBCL or HGBCL. EZH2 expression levels did not differ between diagnostic groups or between DLBCL-NOS molecular groups. We found no associations between EZH2 expression levels and outcome, including in the subgroup analysis (GC versus non-GC). Nonetheless, EZH2\/BCL2 co-expression was significantly associated with worse outcome (event free survival and overall survival). Conclusion: Although EZH2 mutations are almost exclusively found in GC-DLBCL, we found similar EZH2 expression levels in both DLBCL-NOS molecular groups, suggesting non-mutational mechanisms of EZH2 deregulation. These findings suggest that the use of EZH2 antagonists might be extended to non-GC DLBCL patients with clinical benefit. EZH2\/BCL2 co-expression was associated with a worse outcome.<\/jats:p>","DOI":"10.3390\/jpm11121384","type":"journal-article","created":{"date-parts":[[2021,12,19]],"date-time":"2021-12-19T20:37:27Z","timestamp":1639946247000},"page":"1384","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Prognostic Value of Histone Modifying Enzyme EZH2 in RCHOP-Treated Diffuse Large B-Cell Lymphoma and High Grade B-Cell Lymphoma"],"prefix":"10.3390","volume":"11","author":[{"given":"Sara","family":"Petronilho","sequence":"first","affiliation":[{"name":"Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200072 Porto, Portugal"},{"name":"Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center (Porto.CCC), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072, Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4687-3347","authenticated-orcid":false,"given":"Jos\u00e9 Pedro","family":"Sequeira","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center (Porto.CCC), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072, Porto, Portugal"}]},{"given":"Sofia","family":"Paulino","sequence":"additional","affiliation":[{"name":"Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200072 Porto, Portugal"},{"name":"Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center (Porto.CCC), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072, Porto, Portugal"}]},{"given":"Paula","family":"Lopes","sequence":"additional","affiliation":[{"name":"Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200072 Porto, Portugal"},{"name":"Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center (Porto.CCC), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072, Porto, Portugal"}]},{"given":"Susana","family":"Lisboa","sequence":"additional","affiliation":[{"name":"Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200072 Porto, Portugal"}]},{"given":"S\u00e9rgio","family":"Chacim","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center (Porto.CCC), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072, Porto, Portugal"},{"name":"Department of Hematology, Portuguese Oncology Institute of Porto (IPO Porto), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6829-1391","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Lobo","sequence":"additional","affiliation":[{"name":"Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200072 Porto, Portugal"},{"name":"Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center (Porto.CCC), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072, Porto, Portugal"},{"name":"Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4896-5982","authenticated-orcid":false,"given":"Manuel","family":"Teixeira","sequence":"additional","affiliation":[{"name":"Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200072 Porto, Portugal"},{"name":"Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4186-5345","authenticated-orcid":false,"given":"Carmen","family":"Jer\u00f3nimo","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center (Porto.CCC), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072, Porto, Portugal"},{"name":"Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3171-4666","authenticated-orcid":false,"given":"Rui","family":"Henrique","sequence":"additional","affiliation":[{"name":"Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200072 Porto, Portugal"},{"name":"Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center (Porto.CCC), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072, Porto, Portugal"},{"name":"Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,18]]},"reference":[{"key":"ref_1","unstructured":"Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., and Stein, H. (2017). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, International Agency for Research on Cancer. [4th ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1182\/blood-2014-05-577189","article-title":"Diffuse large B-cell lymphoma: Optimizing outcome in the context of clinical and biologic heterogeneity","volume":"125","author":"Sehn","year":"2015","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1182\/blood-2017-11-764332","article-title":"Genetics of DLBCL","volume":"131","author":"Pasqualucci","year":"2018","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/ng.518","article-title":"Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin","volume":"42","author":"Morin","year":"2010","journal-title":"Nat Genet."},{"key":"ref_5","unstructured":"(2020, August 15). cBioPortal. Available online: https:\/\/www.cbioportal.org\/."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1182\/blood-2010-11-321208","article-title":"Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation","volume":"117","author":"Yap","year":"2011","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.3109\/10428194.2014.941836","article-title":"Activating somatic mutations in DLBCL: Lessons from next generation sequencing and key elements in the precision medicine era","volume":"56","author":"Bohers","year":"2015","journal-title":"Leuk. Lymph."},{"key":"ref_8","unstructured":"(2019, October 06). ClinicalTrials.gov, Available online: https:\/\/clinicaltrials.gov\/."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/leu.2010.311","article-title":"EZH2 Y641 mutations in follicular lymphoma","volume":"25","author":"Wrench","year":"2011","journal-title":"Leukemia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.3109\/10428194.2015.1006220","article-title":"Strong expression of EZH2 and accumulation of H3K27me3 in DLBCL independent of COO and EZH2 Y641 mutation","volume":"56","author":"Zhou","year":"2015","journal-title":"Leuk. Lymph."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/s13045-017-0438-7","article-title":"Mutations of CREBBP and SOCS1 are independent prognostic factors in DLBCL: Mutational analysis of the SAKK 38\/07 prospective clinical trial cohort","volume":"10","author":"Juskevicius","year":"2017","journal-title":"J. Hematol. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"16712","DOI":"10.18632\/oncotarget.3154","article-title":"Immunohistochemical and genomic profiles of diffuse large B-cell lymphomas: Implications for targeted EZH2 inhibitor therapy?","volume":"6","author":"Dubois","year":"2015","journal-title":"Oncotarget"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.3109\/10428194.2013.858816","article-title":"Polycomb protein EZH2 expression in diffuse large B-cell lymphoma is associated with better prognosis in patients treated with R-CHOP","volume":"55","author":"Lee","year":"2014","journal-title":"Leuk. Lymph."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1016\/j.humpath.2014.07.002","article-title":"DLBCL with histone H3K27me3 another poor prognostic phenotype independent of c-Myc\/Bcl2 coexpression","volume":"45","author":"Oh","year":"2014","journal-title":"Hum Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1080\/10428194.2016.1180686","article-title":"Loss of RUNX3 expression is an independent adverse prognostic factor in diffuse large B-cell lymphoma","volume":"58","author":"Duncan","year":"2017","journal-title":"Leuk. Lymph."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.humpath.2017.04.011","article-title":"EZH2 overexpression in primary gastrointestinal diffuse large B-cell lymphoma and its association with the clinicopathological features","volume":"64","author":"Liu","year":"2017","journal-title":"Hum. Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3896","DOI":"10.1182\/blood.V97.12.3896","article-title":"Coexpression of BMI-1 and EZH2 polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma","volume":"97","author":"Raaphorst","year":"2001","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1038\/modpathol.2016.114","article-title":"Differential expression of EZH2 protein in small cell and aggressive B-cell NHL and differential regulation of EZH2 expression by p-ERK1\/2 and MYC in aggressive B-cell lymphomas","volume":"29","author":"Tian","year":"2016","journal-title":"Mod. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1111\/apm.12623","article-title":"Clinicopathological features of primary DLBCL of the central nervous system-strong EZH2 expression implying diagnostic and therapeutic implication","volume":"124","author":"Guo","year":"2016","journal-title":"Apmis"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"275","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":"ref_21","doi-asserted-by":"crossref","first-page":"3452","DOI":"10.1200\/JCO.2011.41.0985","article-title":"Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone","volume":"30","author":"Johnson","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3961","DOI":"10.1158\/1078-0432.CCR-05-1977","article-title":"8q Gain Is an Independent Predictor of Poor Survival in Diagnostic Needle Biopsies from Prostate Cancer Suspects","volume":"12","author":"Ribeiro","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.7150\/jca.29807","article-title":"EZH2\/Bcl-2 Coexpression Predicts Worse Survival in Diffuse Large B-cell Lymphomas and Demonstrates Poor Efficacy to Rituximab in Localized Lesions","volume":"10","author":"Deng","year":"2019","journal-title":"J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1038\/nrc.2016.83","article-title":"Maintaining cell identity: PRC2-mediated regulation of transcription and cancer","volume":"16","author":"Comet","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/S1470-2045(18)30145-1","article-title":"Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: A first-in-human, open-label, phase 1 study","volume":"19","author":"Italiano","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1002\/hon.2437_3","article-title":"Interim Report from A Phase 2 Multicenter Study of Tazemetostat, an Ezh2 Inhibitor, in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas","volume":"35","author":"Morschhauser","year":"2017","journal-title":"Hematol. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3111","DOI":"10.1002\/cncr.32145","article-title":"Hitting Back at Lymphoma: How Do Modern Diagnostics Identify High-Risk Diffuse Large B-Cell Lymphoma Subsets and Alter Treatment?","volume":"125","author":"Abramson","year":"2019","journal-title":"Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1634\/theoncologist.2014-0061","article-title":"Biomarker Validation: Common Data Analysis Concerns","volume":"19","author":"Enosr","year":"2014","journal-title":"Oncologist"}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/12\/1384\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:51:41Z","timestamp":1760169101000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/12\/1384"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,18]]},"references-count":28,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["jpm11121384"],"URL":"https:\/\/doi.org\/10.3390\/jpm11121384","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,18]]}}}