EZH2 mutations are frequent and represent an early event in follicular lymphoma.
Gain of function mutations in the H3K27 methyltransferase EZH2 represent a promising therapeutic target in germinal center lymphomas. In this study, we assessed the frequency and distribution of EZH2 mutations in a large cohort of patients with follicular lymphoma (FL) (n = 366) and performed a longitudinal analysis of mutation during the disease progression from FL to transformed FL (tFL) (n = 33). Mutations were detected at 3 recurrent mutation hot spots (Y646, A682, and A692) in 27% of FL cases with variant allele frequencies (VAF) ranging from 2% to 61%. By comparing VAF of EZH2 with other mutation targets (CREBBP, MLL2, TNFRSF14, and MEF2B), we were able to distinguish patients harboring clonal EZH2 mutation from rarer cases with subclonal mutations. Overall, the high incidence of EZH2 mutations in FL and their stability during disease progression makes FL an appropriate disease to evaluate EZH2 targeted therapy.
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, United Kingdom;
Csaba
C
Bödör
Vera
V
Grossmann
Nikolay
N
Popov
Jessica
J
Okosun
Ciarán
C
O'Riain
King
K
Tan
Jacek
J
Marzec
Shamzah
S
Araf
Jun
J
Wang
Abigail M
AM
Lee
Andrew
A
Clear
Silvia
S
Montoto
Janet
J
Matthews
Sameena
S
Iqbal
Hajnalka
H
Rajnai
Andreas
A
Rosenwald
German
G
Ott
Elias
E
Campo
Lisa M
LM
Rimsza
Erlend B
EB
Smeland
Wing C
WC
Chan
Rita M
RM
Braziel
Louis M
LM
Staudt
George
G
Wright
T Andrew
TA
Lister
Olivier
O
Elemento
Robert
R
Hills
John G
JG
Gribben
Claude
C
Chelala
András
A
Matolcsy
Alexander
A
Kohlmann
Torsten
T
Haferlach
Randy D
RD
Gascoyne
Jude
J
Fitzgibbon
D014408:Biomarkers, Tumor / Q000235:genetics*; D050882:CREB-Binding Protein / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein; D020869:Gene Expression Profiling; D005787:Gene Frequency; D006801:Humans; D053208:Kaplan-Meier Estimate; D008224:Lymphoma, Follicular / Q000235:genetics* / Q000473:pathology; D064326:MEF2 Transcription Factors / Q000235:genetics; D009154:Mutation; D063151:Polycomb Repressive Complex 2 / Q000235:genetics*; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000235:genetics; D013997:Time Factors
D014408:Biomarkers, Tumor; D064326:MEF2 Transcription Factors; C578038:MEF2B protein, human; D053240:Receptors, Tumor Necrosis Factor, Member 14; C506028:TNFRSF14 protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D050882:CREB-Binding Protein; C494363:CREBBP protein, human