Abstract 1002: Epigenetic and genetic characteristics and their association with prognosis of follicular lymphoma: Analysis at a Japanese single institution
Authors: Watanabe Mizuki , Goda Naoki , Kanda Junya , Yoshizawa Akihiko , Nishikori Momoko , Nannya Yasuhito , Yoshida Kenichi , Ogawa Seishi , Haga Hironori , Takaori-Kondo Akifumi 
Published: April 2023

Abstract
[Background] Epigenetic and genetic characteristics in Japanese follicular lymphoma (FL) patients have been scarcely evaluated. EHZ2 represents a new therapeutic target in FL and identifying candidates for EZH2 inhibition medication in the general hospital settings without access to genetic sequencing is critical. Since EZH2 regulates methylation at the 27th amino acid in Histone (H3K27), we evaluated the characteristics of EZH2 expression and H3K27 methylation in the Japanese FL cohort as well as their association with genetic characteristics. Prognostic impact of these factors on clinical outcomes was also examined.
[Method and Patients] A total of 164 patients (female, n=91; male, n=73) diagnosed with FL at Kyoto University Hospital between 2005 and 2020 were included. A total of 105 patients were assessed immunohistochemically using H-score for EZH2 expression (EZH2-score) and H3K27me3/me2 scoring (Methylation-score). Impact of these scores at diagnosis on overall survival (OS) and progression/relapse after the 1st immunochemotherapy were examined. We also performed next generation sequencing for 357 genes for 116 samples at diagnosis and examined their correlation with immunohistochemical characteristics.
[Results] Median age at diagnosis was 61 years (range, 33-86) and the median follow-up years was 7.5. Median EZH2-score was 70 (range, 0-290) and median Methylation-score was 2.38 (range, -4.25-4.95), with no apparent correlation. Twenty-five patients (21.6%) harbored EZH2 mutations at diagnosis, all of which were in the mutation hotspots and showed a strong correlation with high Methylation-scores (p-value &lt; 0.001). Based on the prognostic impact of Methylation- and EZH2-score on survival, patients were divided into 3 groups: Group I, those with low Methylation-scores (&lt;2) and high EZH2-scores (≥100); Group II, those with low Methylation-scores (&lt;2) and low EZH2-scores (&lt;100); Group III, those with high Methylation scores (≥100). Group I showed inferior OS compared to Group III (p=0.038) with high risk of rapid relapse/progression (62.5%) within 2 years, who frequently harbored mutations in CSMD3 (vs Group III: p=0.004), KMT2D (p&lt;0.001) and SETD1B (p&lt;0.001). Distribution of mutated genes among Group III patients differed according to the existence of EZH2 mutation, with high frequency of mutated USH2A (p=0.019) and MGAM (p=0.019) genes in those with EZH2 mutation, whereas mutations in TP53 were observed only in those without (p=0.072).
[Conclusion] Methylation-score could be helpful in distinguishing patients with and without EZH2 mutations and enables clinicians to identify candidates for EZH2 inhibition medications. Combination of EZH2- and Methylation-scores predicts clinical outcomes after the 1st immunochemotherapy, which also could potentially identify genetically distinct population in the heterogeneous FL cohort.
Citation Format: Mizuki Watanabe, Naoki Goda, Junya Kanda, Akihiko Yoshizawa, Momoko Nishikori, Yasuhito Nannya, Kenichi Yoshida, Seishi Ogawa, Hironori Haga, Akifumi Takaori-Kondo. Epigenetic and genetic characteristics and their association with prognosis of follicular lymphoma: Analysis at a Japanese single institution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1002.