EZH2 mutations are frequent and represent an early event in follicular lymphoma

被引：259

作者：

Boedoer, Csaba ^{[1
,2
]}

Grossmann, Vera ^{[3
,4
]}

Popov, Nikolay ^{[1
]}

Okosun, Jessica ^{[1
]}

O'Riain, Ciaran ^{[1
]}

Tan, King ^{[5
]}

Marzec, Jacek ^{[6
]}

Araf, Shamzah ^{[1
]}

Wang, Jun ^{[6
]}

Lee, Abigail M. ^{[1
]}

Clear, Andrew ^{[1
]}

Montoto, Silvia ^{[1
]}

Matthews, Janet ^{[1
]}

Iqbal, Sameena ^{[1
]}

Rajnai, Hajnalka ^{[2
]}

Rosenwald, Andreas ^{[7
]}

Ott, German ^{[7
,8
,9
]}

Campo, Elias ^{[10
]}

Rimsza, Lisa M. ^{[11
]}

Smeland, Erlend B. ^{[12
,13
]}

Chan, Wing C. ^{[14
]}

Braziel, Rita M. ^{[15
]}

Staudt, Louis M. ^{[16
]}

Wright, George ^{[16
]}

Lister, T. Andrew ^{[1
]}

Elemento, Olivier ^{[17
,18
]}

Hills, Robert ^{[19
]}

Gribben, John G. ^{[1
]}

Chelala, Claude ^{[6
]}

Matolcsy, Andras ^{[2
]}

Kohlmann, Alexander ^{[3
]}

Haferlach, Torsten ^{[3
]}

Gascoyne, Randy D. ^{[5
]}

Fitzgibbon, Jude ^{[1
]}

机构：

[1] Queen Mary Univ London, Barts Canc Inst, Ctr Haematooncol, London EC1M 6BQ, England

[2] Semmelweis Univ, Dept Pathol & Expt Canc Res, H-1085 Budapest, Hungary

[3] MLL Munich Leukemia Lab GmbH, Munich, Germany

[4] Johannes Gutenberg Univ Mainz, Univ Med Ctr Mainz, Ctr Thrombosis & Hemostasis, D-55122 Mainz, Germany

[5] British Columbia Canc Ctr, Dept Pathol, Vancouver, BC, Canada

[6] Queen Mary Univ London, Barts Canc Inst, Ctr Mol Oncol, London EC1M 6BQ, England

[7] Univ Wurzburg, Inst Pathol, Wurzburg, Germany

[8] Dept Clin Pathol, Stuttgart, Germany

[9] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany

[10] Univ Barcelona, Hosp Clin, Dept Pathol, Barcelona, Spain

[11] Univ Arizona, Ctr Canc, Dept Pathol, Tucson, AZ USA

[12] Oslo Univ Hosp, Inst Canc Res, Dept Immunol, Oslo, Norway

[13] Univ Oslo, Fac Med, Ctr Canc Biomed, Oslo, Norway

[14] Univ Nebraska Med Ctr, Dept Pathol, Omaha, NE USA

[15] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA

[16] Natl Canc Inst, Metab Branch, Bethesda, MD USA

[17] Weill Cornell Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY USA

[18] Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY USA

[19] Cardiff Univ, Sch Med, Dept Haematol, Cardiff CF10 3AX, S Glam, Wales

来源：

BLOOD | 2013年 / 122卷 / 18期

关键词：

SOMATIC MUTATIONS; HISTONE H3; LYSINE; 27; HYPERTRIMETHYLATION; INHIBITION; SURVIVAL; GENES; TET2;

D O I：

10.1182/blood-2013-04-496893

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 othermutation 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.

引用

页码：3165 / 3168

页数：4

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