Comparative Analysis of the Clinicopathological Features of Follicular Lymphoma With and Without EZH2 Y646 Mutation

Histone methyltransferase EZH2 is essential for germinal center formation, and gain-of-function mutations of EZH2 occur in approximately 20% of follicular lymphomas (FLs). Although EZH2 inhibitors are used for relapsed/refractory EZH2-mutated (EZH2^mut) FLs, their clinicopathological characteristics remain incompletely understood. We assessed the EZH2 Y646 mutation by Sanger sequencing in 301 FLs and identified mutations in 17% (50/301). Compared with EZH2 wild-type (EZH2^wt), EZH2^mut FL showed a significantly higher proportion aged > 60 years (p = 0.033). Pathologically, EZH2^mut FL more frequently exhibited clear neoplastic follicles (p < 0.0001) and grater interfollicular tumor cell distributions highlighted by CD20 immunohistochemistry (p < 0.0001). These cases also more often showed the typical FL immunophenotype (CD10+, BCL2+, BCL6+) (p = 0.027) and BCL2 rearrangement (p = 0.0060). Gene expression profiling revealed enrichment of TNF-α/NF-κB signaling in EZH2^wt FL, whereas EZH2^mut FL showed upregulation of cell-cycle programs, particularly the G2/M checkpoint. Concordance of EZH2 mutation status between primary and relapsed lesions was 94% (33/35). Even at relapse, EZH2^mut FL retained its characteristic pathological features, including clear follicles and high interfollicular spread of tumor cells. In conclusion, EZH2^mut FL exhibits distinctive clinicopathological and molecular features that may help identify patients most likely to benefit from EZH2-targeted therapy.