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 Charles Greiner, Wing C. Chan

Research output: Contribution to journalArticle

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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

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Follicular Lymphoma
Ethnic Groups
Gene Expression
Mutation
Gene Expression Profiling
Codon
Enhancer of Zeste Homolog 2 Protein
Genes
Germinal Center
Lymphoma, Large B-Cell, Diffuse
Non-Hodgkin's Lymphoma
Research Design
Immunohistochemistry

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

EZH2 mutations in follicular lymphoma from different ethnic groups and associated gene expression alterations. / Guo, Shuangping; Chan, John K C; Iqbal, Javeed; McKeithan, Timothy; Fu, Kai; Meng, Bin; Pan, Yi; Cheuk, Wah; Luo, Donglan; Wang, Ruian; Zhang, Weiwei; Greiner, Timothy Charles; Chan, Wing C.

In: Clinical Cancer Research, Vol. 20, No. 12, 15.06.2014, p. 3078-3086.

Research output: Contribution to journalArticle

Guo, Shuangping ; Chan, John K C ; Iqbal, Javeed ; McKeithan, Timothy ; Fu, Kai ; Meng, Bin ; Pan, Yi ; Cheuk, Wah ; Luo, Donglan ; Wang, Ruian ; Zhang, Weiwei ; Greiner, Timothy Charles ; Chan, Wing C. / EZH2 mutations in follicular lymphoma from different ethnic groups and associated gene expression alterations. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 12. pp. 3078-3086.
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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.",
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T1 - EZH2 mutations in follicular lymphoma from different ethnic groups and associated gene expression alterations

AU - Guo, Shuangping

AU - Chan, John K C

AU - Iqbal, Javeed

AU - McKeithan, Timothy

AU - Fu, Kai

AU - Meng, Bin

AU - Pan, Yi

AU - Cheuk, Wah

AU - Luo, Donglan

AU - Wang, Ruian

AU - Zhang, Weiwei

AU - Greiner, Timothy Charles

AU - Chan, Wing C.

PY - 2014/6/15

Y1 - 2014/6/15

N2 - 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.

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