EZH2 Expression in Follicular Lymphoma Is Variable and Independent from the Progression of Disease Within 24 Months of First Treatment

Abstract

Background/Aim: Follicular lymphoma (FL) relapse within 24 months of the first immunochemotherapy (POD24) indicates more precisely poor overall survival and high risk of death. The aim of the study was to assess the potential value of POD24 in FL and describe the enhancer of zeste homolog 2 (EZH2) expression profile, in correlation with clinical/ histopathological/immunophenotypical characteristics. Materials and Methods: This retrospective single-center study included 75 patients with FL treated under watch and wait (W&W) and immunochemotherapy regimens. All cases were immunohistochemically assessed: assays were performed for EZH2, CD10, BCL6, BCL2, MUM1, MYC and p53. Results: POD24 was independent of clinical/histopathological/ immunohistochemical features and separated patients with inferior outcomes. EZH2 high expression was observed in high/low grade and follicular/diffuse FL patterns. BCL2negative (p=0.042) and MUM1 (p=0.039), MYC (p<0.001), p53 (p<0.001) -positive cases had significantly higher EZH2 expression. Conclusion: POD24 is currently the most useful tool for the identification of poor outlook patients. EZH2 is crucial in FL biology, but the value of its protein expression is limited as a prognostic factor. Follicular lymphoma (FL) is an indolent B-cell lymphoma, but early relapse after first-line therapy occurs in up to 20% of patients (1-3). Different prognostic markers have been evaluated; however, the follicular International Prognostic Index (FLIPI) is still the only reproducible tool (4, 5). Its molecular modifications have not been yet widely accessible, while the next-generation sequencing-based genetic evaluation of FL is not a routine part of a diagnostic examination (6-8). Recently, the progression of disease within 24 months of first treatment (POD24) was applied for the identification of FL high-risk patients (3, 9). Early treatment failure is predictive of poor overall survival (10) and seems to be independent of initial treatment modality (11). Available results indicating the association of POD24 with prognostic markers, i.e., reduced intratumoral immune infiltration, pre-treatment positronemission tomography-based staging, and molecular status, are still inconsistent and unsatisfactory (12,13).Enhancer of zeste homolog 2 (EZH2) is a histone-lysine Nmethyltransferase enzyme encoded by the EZH2 gene. It is a functional component of polycomb repressive complex 2 (PRC2) and catalyzes the methylation of histone H3 lysine 27 6685

Prognostic impact of nutritional and inflammation-based risk scores in follicular lymphoma in the era of anti-CD20 targeted treatment strategies

“…Several studies aimed to predict POD24 by analyzing different biomarkers and genomic signatures. One such genetic biomarker that holds the potential to significantly influence therapeutic responses is an underlying EZH2 mutation (Szumera-CieCkiewicz et al 2020 ). Apart from that, a distinct genomic signature for the prediction of POD24 remains undetected.…”

“…Treatment approaches are stage adapted and depend on comorbidities as well as performance status (PS) (Batlevi et al 2020;Freedman 2018). Recently, alterations in EZH2 gene locus could be identified as driver mutations harboring the capability to guide therapeutic decision making in advanced stage FL (Jurinovic et al 2019;Szumera-CieCkiewicz et al 2020). Comprehensive genomic profiling revealed distinct heterogeneity in FL with or without the genetic hallmark of FL represented by the chromosomal translocation t(14;18)(q32;q21), which leads to an overexpression of the BCL-2 protein (Kretzmer et al 2015;Nann et al 2020;Qu et al 2019;Stevens et al 2017).…”

Gastrointestinal Follicular Lymphoma: A Single-institutional Experience of 22 Cases With Emphasis on the Comprehensive Clinicopathological Analysis and Diagnostic Re-classification

“…Follicular lymphoma (FL) is a systemic neoplasm of the lymphoid tissue derived from germinal center (GC) B-cells (1,2). FL is histologically characterized by numerous, densely packed abnormal follicles consisting of variable numbers of centrocytes and centroblasts (1,3). Neoplastic follicles express anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) reflecting its underlying pathogenic t(14;18) translocation (4).…”