title: Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin.
abstract: Follicular lymphoma (FL) and the GCB subtype of diffuse large B-cell lymphoma (DLBCL) derive from germinal center B cells. Targeted resequencing studies have revealed mutations in various genes encoding proteins in the NF-kappaB pathway that contribute to the activated B-cell (ABC) DLBCL subtype, but thus far few GCB-specific mutations have been identified. Here we report recurrent somatic mutations affecting the polycomb-group oncogene EZH2, which encodes a histone methyltransferase responsible for trimethylating Lys27 of histone H3 (H3K27). After the recent discovery of mutations in KDM6A (UTX), which encodes the histone H3K27me3 demethylase UTX, in several cancer types, EZH2 is the second histone methyltransferase gene found to be mutated in cancer. These mutations, which result in the replacement of a single tyrosine in the SET domain of the EZH2 protein (Tyr641), occur in 21.7% of GCB DLBCLs and 7.2% of FLs and are absent from ABC DLBCLs. Our data are consistent with the notion that EZH2 proteins with mutant Tyr641 have reduced enzymatic activity in vitro.
authors.affiliation: Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morin
authors.forename: Nathalie A
authors.initials: NA
authors.lastname: Johnson
authors.forename: Tesa M
authors.initials: TM
authors.lastname: Severson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Mungall
authors.forename: Jianghong
authors.initials: J
authors.lastname: An
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Goya
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Paul
authors.forename: Merrill
authors.initials: M
authors.lastname: Boyle
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Woolcock
authors.forename: Florian
authors.initials: F
authors.lastname: Kuchenbauer
authors.forename: Damian
authors.initials: D
authors.lastname: Yap
authors.forename: R Keith
authors.initials: RK
authors.lastname: Humphries
authors.forename: Obi L
authors.initials: OL
authors.lastname: Griffith
authors.forename: Sohrab
authors.initials: S
authors.lastname: Shah
authors.forename: Henry
authors.initials: H
authors.lastname: Zhu
authors.forename: Michelle
authors.initials: M
authors.lastname: Kimbara
authors.forename: Pavel
authors.initials: P
authors.lastname: Shashkin
authors.forename: Jean F
authors.initials: JF
authors.lastname: Charlot
authors.forename: Marianna
authors.initials: M
authors.lastname: Tcherpakov
authors.forename: Richard
authors.initials: R
authors.lastname: Corbett
authors.forename: Angela
authors.initials: A
authors.lastname: Tam
authors.forename: Richard
authors.initials: R
authors.lastname: Varhol
authors.forename: Duane
authors.initials: D
authors.lastname: Smailus
authors.forename: Michelle
authors.initials: M
authors.lastname: Moksa
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Allen
authors.initials: A
authors.lastname: Delaney
authors.forename: Hong
authors.initials: H
authors.lastname: Qian
authors.forename: Inanc
authors.initials: I
authors.lastname: Birol
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Schein
authors.forename: Richard
authors.initials: R
authors.lastname: Moore
authors.forename: Robert
authors.initials: R
authors.lastname: Holt
authors.forename: Doug E
authors.initials: DE
authors.lastname: Horsman
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Connors
authors.forename: Steven
authors.initials: S
authors.lastname: Jones
authors.forename: Samuel
authors.initials: S
authors.lastname: Aparicio
authors.forename: Martin
authors.initials: M
authors.lastname: Hirst
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005091:Exons / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics; D018858:Germinal Center / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D063151:Polycomb Repressive Complex 2; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*; D014443:Tyrosine / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D050505:Mutant Proteins; D014157:Transcription Factors; D014443:Tyrosine; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2