title: EZH2 mutations in follicular lymphoma from different ethnic groups and associated gene expression alterations.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 < 0.01) in mutated cases, and the potential target TCL1A showed consistent results at the protein level.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Authors' Affiliations: Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province; Department of Pathology, Queen Elizabeth Hospital, Hong Kong; Department of Pathology, Shandong University School of Medicine, Jinan, Shandong Province; Department of Pathology, Tianjin Cancer Hospital; Department of Pathology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NebraskaAuthors' Affiliations: Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province; Department of Pathology, Queen Elizabeth Hospital, Hong Kong; Department of Pathology, Shandong University School of Medicine, Jinan, Shandong Province; Department of Pathology, Tianjin Cancer Hospital; Department of Pathology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Shuangping
authors.initials: S
authors.lastname: Guo
authors.affiliation: Authors' Affiliations: Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province; Department of Pathology, Queen Elizabeth Hospital, Hong Kong; Department of Pathology, Shandong University School of Medicine, Jinan, Shandong Province; Department of Pathology, Tianjin Cancer Hospital; Department of Pathology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: John K C
authors.initials: JK
authors.lastname: Chan
authors.affiliation: Authors' Affiliations: Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province; Department of Pathology, Queen Elizabeth Hospital, Hong Kong; Department of Pathology, Shandong University School of Medicine, Jinan, Shandong Province; Department of Pathology, Tianjin Cancer Hospital; Department of Pathology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Javeed
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: Authors' Affiliations: Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province; Department of Pathology, Queen Elizabeth Hospital, Hong Kong; Department of Pathology, Shandong University School of Medicine, Jinan, Shandong Province; Department of Pathology, Tianjin Cancer Hospital; Department of Pathology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Timothy
authors.initials: T
authors.lastname: McKeithan
authors.affiliation: Authors' Affiliations: Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province; Department of Pathology, Queen Elizabeth Hospital, Hong Kong; Department of Pathology, Shandong University School of Medicine, Jinan, Shandong Province; Department of Pathology, Tianjin Cancer Hospital; Department of Pathology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Kai
authors.initials: K
authors.lastname: Fu
authors.affiliation: Authors' Affiliations: Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province; Department of Pathology, Queen Elizabeth Hospital, Hong Kong; Department of Pathology, Shandong University School of Medicine, Jinan, Shandong Province; Department of Pathology, Tianjin Cancer Hospital; Department of Pathology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Bin
authors.initials: B
authors.lastname: Meng
authors.affiliation: Authors' Affiliations: Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province; Department of Pathology, Queen Elizabeth Hospital, Hong Kong; Department of Pathology, Shandong University School of Medicine, Jinan, Shandong Province; Department of Pathology, Tianjin Cancer Hospital; Department of Pathology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Authors' Affiliations: Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province; Department of Pathology, Queen Elizabeth Hospital, Hong Kong; Department of Pathology, Shandong University School of Medicine, Jinan, Shandong Province; Department of Pathology, Tianjin Cancer Hospital; Department of Pathology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Wah
authors.initials: W
authors.lastname: Cheuk
authors.affiliation: Authors' Affiliations: Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province; Department of Pathology, Queen Elizabeth Hospital, Hong Kong; Department of Pathology, Shandong University School of Medicine, Jinan, Shandong Province; Department of Pathology, Tianjin Cancer Hospital; Department of Pathology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Donglan
authors.initials: D
authors.lastname: Luo
authors.affiliation: Authors' Affiliations: Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province; Department of Pathology, Queen Elizabeth Hospital, Hong Kong; Department of Pathology, Shandong University School of Medicine, Jinan, Shandong Province; Department of Pathology, Tianjin Cancer Hospital; Department of Pathology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Ruian
authors.initials: R
authors.lastname: Wang
authors.affiliation: Authors' Affiliations: Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province; Department of Pathology, Queen Elizabeth Hospital, Hong Kong; Department of Pathology, Shandong University School of Medicine, Jinan, Shandong Province; Department of Pathology, Tianjin Cancer Hospital; Department of Pathology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Authors' Affiliations: Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province; Department of Pathology, Queen Elizabeth Hospital, Hong Kong; Department of Pathology, Shandong University School of Medicine, Jinan, Shandong Province; Department of Pathology, Tianjin Cancer Hospital; Department of Pathology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Greiner
authors.affiliation: Authors' Affiliations: Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province; Department of Pathology, Queen Elizabeth Hospital, Hong Kong; Department of Pathology, Shandong University School of Medicine, Jinan, Shandong Province; Department of Pathology, Tianjin Cancer Hospital; Department of Pathology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska jochan@coh.org.
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018858:Germinal Center; D006801:Humans; D007124:Immunoenzyme Techniques; D008224:Lymphoma, Follicular / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D063151:Polycomb Repressive Complex 2 / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2