J Cancer 2019; 10(9):2006-2017. doi:10.7150/jca.29807

Research Paper

EZH2/Bcl-2 Coexpression Predicts Worse Survival in Diffuse Large B-cell Lymphomas and Demonstrates Poor Efficacy to Rituximab in Localized Lesions

Yujie Deng1#, Xiaohui Chen2#, Chuanzhong Huang3, Gang Chen4, Fangfang Chen4, Jianping Lu4, Xi Shi1, Cheng He4, Zhiyong Zeng5, Yanhua Qiu6, Junqiang Chen7, Rongbo Lin8, Yanping Chen4, Junmin Chen5✉

1. Department of Chemotherapy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
2. Department of Thoracic Surgery, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, China
3. Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, China
4. Department of Pathology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, China
5. Department of Hematology and Rheumatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
6. Department of Medical Imaging, Grade 2014, Fujian Medical University, Fuzhou, China
7. Department of Thoracic Radiotherapy, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, China
8. Department of Gastrointestinal Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, China
# These two authors contributed equally to this paper.

Abstract

Enhancer of zeste homolog 2 (EZH2) and Bcl-2 gene rearrangement or protein upregulation played pivotal roles in the carcinogenesis of various malignancies including lymphomas. However, EZH2/Bcl-2 expression pattern and its clinicopathologic/prognostic significance in diffuse large B-cell lymphoma (DLBCL) remain unclear. To identify the association among EZH2, Bcl-2, clinicopathologic parametres in DLBCL, 2 DLBCL patient sets (test cohort, n=85; validation cohort n=51) and DLBCL cell lines were studied by tumor tissue microarray (TMA), immunohistochemistry and western blot. The optimal cut-off of EZH2 was determined by X-tile program from test cohort, as was verified in validation cohort. The prognostic significance was determined via Kaplan-Meier survival estimates and log-rank tests. Consequently, EZH2 and Bcl-2 expression were both enhanced and positively correlated with each other (𝑃=0.001) in both DLBCL patients and cell lines. EZH2/Bcl-2 coexpression was associated with poor overall survival (OS) and progression-free survival (PFS) in all DLBCL patients (all P<0.05). Univariate analyses revealed that EZH2/Bcl-2 coexpression correlated to worse objective response rate (ORR), shorter OS and PFS in DLBCL patients treated with RCHOP while multivariate analysis indicated that only elevated LDH level (P=0.001) and presence of B symtom (P=0.008) rather than EZH2/Bcl-2 coexpression were associated with worse OS. No survival benefit from rituximab regimen had been demonstrated in the early-staged DLBCL patients with EZH2/Bcl-2 coexpression. While in the subgroup of III-IV stage, RCHOP regimen showed obvious better OS and PFS than CHOP (P=0.039 and 0.005). In conclusion, EZH2/Bcl-2 coexpression defines unrecognized subgroup of DLBCL patients with distinct epigenetic phenotype and worse outcome.

Keywords: diffuse large B-cell lymphoma·EZH2·Bcl-2·prognosis·rituximab

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How to cite this article:
Deng Y, Chen X, Huang C, Chen G, Chen F, Lu J, Shi X, He C, Zeng Z, Qiu Y, Chen J, Lin R, Chen Y, Chen J. EZH2/Bcl-2 Coexpression Predicts Worse Survival in Diffuse Large B-cell Lymphomas and Demonstrates Poor Efficacy to Rituximab in Localized Lesions. J Cancer 2019; 10(9):2006-2017. doi:10.7150/jca.29807. Available from http://www.jcancer.org/v10p2006.htm