Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin.
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.
Morin
Ryan D
RD
Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
Johnson
Nathalie A
NA
Severson
Tesa M
TM
Mungall
Andrew J
AJ
An
Jianghong
J
Goya
Rodrigo
R
Paul
Jessica E
JE
Boyle
Merrill
M
Woolcock
Bruce W
BW
Kuchenbauer
Florian
F
Yap
Damian
D
Humphries
R Keith
RK
Griffith
Obi L
OL
Shah
Sohrab
S
Zhu
Henry
H
Kimbara
Michelle
M
Shashkin
Pavel
P
Charlot
Jean F
JF
Tcherpakov
Marianna
M
Corbett
Richard
R
Tam
Angela
A
Varhol
Richard
R
Smailus
Duane
D
Moksa
Michelle
M
Zhao
Yongjun
Y
Delaney
Allen
A
Qian
Hong
H
Birol
Inanc
I
Schein
Jacqueline
J
Moore
Richard
R
Holt
Robert
R
Horsman
Doug E
DE
Connors
Joseph M
JM
Jones
Steven
S
Aparicio
Samuel
S
Hirst
Martin
M
Gascoyne
Randy D
RD
Marra
Marco A
MA
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
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