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EZH2 expression is associated with inferior overall survival in mantle cell lymphoma

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Abstract

Enhancer of zeste homolog 2 (EZH2) is a catalytic component of the polycomb repressive complex 2 (PRC2) which reduces gene expression via trimethylation of a lysine residue of histone 3 (H3K27me3). Expression of EZH2 has not been assessed systematically in mantle cell lymphoma (MCL). Expression of EZH2 was assessed by immunohistochemistry in 166 patients with MCL. We also assessed other PRC2 components and H3K27me3. Fifty-seven (38%) of MCL patients were positive for EZH2 using 40% cutoff. EZH2 expression was associated with aggressive histologic variants (65% vs. 29%, p < 0.001), high Ki-67 proliferation rate (median, 72% vs. 19%, p < 0.001), and p53 overexpression (43% vs. 2%, p < 0.001). EZH2 expression did not correlate with expression of other PRC2 components (EED and SUZ12), H3K27me3, MHC-I, and MHC-II. Patients with EZH2 expression (EZH2+) had a poorer overall survival (OS) compared with patients without EZH2 expression (EZH2−) (median OS: 3.9 years versus 9.4 years, respectively, p < 0.001). EZH2 expression also predicted a poorer prognosis in MCL patients with classic histology (median OS, 4.6 years for EZH2+ and 9.6 years for EZH2-negative, respectively, p < 0.001) as well as aggressive histology (median OS, 3.7 years for EZH2+ and 7.9 years for EZH2-negative, respectively, p = 0.046). However, EZH2 expression did not independently correlate with overall survival in a multivariate analysis. Gene expression analysis and pathway enrichment analysis demonstrated a significant enrichment in cell cycle and mitotic transition pathways in MCL with EZH2 expression. EZH2 expression detected by immunohistochemistry is present in 38% of MCL cases and it is associated with high proliferation rate, p53 overexpression, aggressive histologic variants, and poorer OS. Based on gene expression profiling data, EZH2 expression could potentiate cell cycle machinery in MCL. These data suggest that assessment of EZH2 expression could be useful to stratify MCL patients into low- and high-risk groups.

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Fig. 1: Mantle cell lymphoma (MCL) with EZH2 expression (EZH2+ MCL).
Fig. 2: Mantle cell lymphoma without EZH2 expression (EZH2(−) MCL.
Fig. 3: Kaplan–Meier curves in mantle cell lymphoma.
Fig. 4: Volcano plot for differential expression between EZH2-overexpressed group and EZH2 not overexpressed group.

Data availability

All data generated or analyzed during this study are included in this published article.

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Acknowledgements

This study was supported by MD Anderson’s Histopathology Core Lab (RHCL), Award Number 2P30CA016672-38 from the NIH National Cancer Institute. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

Funding

This study was supported by UT MDACC institutional grant to C.Y.O.

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D.M.B., A.S. and C.Y.O. conceived the study concept and design. D.M.B., A.S., D.H.K., D.P.O., A.D. and C.Y.O. provided acquisition and interpretation of data. H.M., D.H.K. and C.Y.O. performed the statistical analyses. R.K.S., S.L., K.H.Y., D.P.O., A.D., P.J., M.L.W., T.J.M., R.N.M., F.V., L.J.M. and C.Y.O. performed writing, review, and revision of the paper. All authors read and approved the final paper.

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Correspondence to Chi Young Ok.

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This study was approved by the Institutional Review Board (protocol 2019-1191) at the University of Texas MD Anderson Cancer Center, which waived the requirement of written informed consent.

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Martinez-Baquero, D., Sakhdari, A., Mo, H. et al. EZH2 expression is associated with inferior overall survival in mantle cell lymphoma. Mod Pathol (2021). https://doi.org/10.1038/s41379-021-00885-9

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