EZH2 mutations in follicular lymphoma from different ethnic groups and associated gene expression alterations

Shuangping Guo, John K.C. Chan, Javeed Iqbal, Timothy McKeithan, Kai Fu, Bin Meng, Yi Pan, Wah Cheuk, Donglan Luo, Ruian Wang, Weiwei Zhang, Timothy C. Greiner, Wing C. Chan

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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 withWestern 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%, χ2 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%, χ2 test, P = 0.02). EZH2 mutations also showed significant association with BCL2 rearrangement in the Chinese cohort (26.8% vs. 8.8%, χ2 test, P = 0.008) and combined cohorts (26.3% vs. 9.1%, χ2 test, P = 0.002). GEP analysis identified several genes, including TCF4, FOXP1, TCL1A, BIK, and RASSF6P, with significantly lower mRNA expression (P < 0.01) in mutated cases, and the potential target TCL1A showed consistent results at the protein level. 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.

Original languageEnglish (US)
Pages (from-to)3078-3086
Number of pages9
JournalClinical Cancer Research
Volume20
Issue number12
DOIs
StatePublished - Jun 15 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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