EZH2 Mutations in Follicular Lymphoma from Different Ethnic Groups and Associated Gene Expression Alterations

Purpose: Gain-of-function mutations of enhancer of Zeste homolog 2 ( EZH2 ) occur frequently in diffuse large B-cell lymphomas and in follicular lymphomas. However, the frequency of EZH2 mutation in Chinese follicular lymphomas and the potential targets affected by this mutation are unknown. Experimental Design: We determined EZH2 codon 641 mutations in Chinese follicular lymphomas ( n = 124) and compared them with Western follicular lymphomas ( n = 70) using a sensitive pyrosequencing assay. Gene expression profiling (GEP) was performed to determine differential gene expression between the mutated versus unmutated subgroups, and selected genes were validated using immunohistochemistry. Results: Our results showed similar frequencies of EZH2 codon 641 mutations in Chinese and Western follicular lymphoma cohorts (16.9% vs. 18.6%, χ 2 test, P = 0.773), including all five reported mutation variants. We observed significant association of EZH2 mutation with low morphologic grade follicular lymphomas (grade 1–2, 23.6% vs. grade 3, 7.7%, χ 2 test, P = 0.02). EZH2 mutations also showed significant association with BCL2 rearrangement in the Chinese cohort (26.8% vs. 8.8%, χ 2 test, P = 0.008) and combined cohorts (26.3% vs. 9.1%, χ 2 test, P = 0.002). GEP analysis identified several genes, including TCF4, FOXP1, TCL1A, BIK , and RASSF6P , with significantly lower mRNA expression ( P Conclusion: Similar prevalence of EZH2 mutation in two ethnic groups suggests shared pathogenetic mechanisms. The much lower frequency of EZH2 mutation in cases without BCL2 translocation suggests a different pattern of evolution of this subtype of follicular lymphoma. GEP studies showed a set of differentially expressed genes and suggested that EZH2 mutation may help to lock the tumor cells at the germinal center stage of differentiation. Clin Cancer Res; 20(12); 3078–86. ©2014 AACR .