Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG)

被引：151

作者：

Gaidzik, Verena I. ^{[1
]}

Schlenk, Richard F. ^{[1
]}

Paschka, Peter ^{[1
]}

Stoelzle, Anja ^{[1
]}

Spaeth, Daniela ^{[1
]}

Kuendgen, Andrea ^{[2
]}

von Lilienfeld-Toal, Marie ^{[3
]}

Brugger, Wolfram ^{[4
]}

Derigs, Hans Guenter ^{[5
]}

Kremers, Stephan ^{[6
]}

Greil, Richard ^{[7
]}

Raghavachar, Aruna ^{[8
]}

Ringhoffer, Mark ^{[9
]}

Salih, Helmut R. ^{[10
]}

Wattad, Mohammed ^{[11
]}

Kirchen, Heinz G. ^{[12
]}

Runde, Volker ^{[13
]}

Heil, Gerhard ^{[14
]}

Petzer, Andreas L. ^{[15
]}

Girschikofsky, Michael ^{[16
]}

Heuser, Michael ^{[17
]}

Kayser, Sabine ^{[1
]}

Goehring, Gudrun ^{[17
]}

Teleanu, Maria-Veronica ^{[1
]}

Schlegelberger, Brigitte ^{[17
]}

Ganser, Arnold ^{[17
]}

Krauter, Juergen ^{[17
]}

Bullinger, Lars ^{[1
]}

Doehner, Hartmut ^{[1
]}

Doehner, Konstanze ^{[1
]}

机构：

[1] Univ Ulm Klinikum, Ulm, Germany

[2] Univ Klinikum Dusseldorf, Dusseldorf, Germany

[3] Univ Klinikum Bonn, Bonn, Germany

[4] Schwarzwald Baar Klinikum Villingen Schwenningen, Villingen Schwenningen, Germany

[5] Klinikum Frankfurt Hochst GmbH, Frankfurt, Germany

[6] Caritas Krankenhaus Lebach, Lebach, Germany

[7] Paracelsus Med Univ Salzburg, Univ Klinikum, Salzburg, Austria

[8] Helios Klinikum Wuppertal, Wuppertal, Germany

[9] Stadt Klinikum Karlsruhe GmbH, Karlsruhe, Germany

[10] Univ Klinikum Tubingen, Tubingen, Germany

[11] Ev Krankenhaus Essen Werden GmbH, Kliniken Essen Sud, Essen, Germany

[12] Krankenhaus Barmherzigen Bruder, Trier, Germany

[13] Wilhelm Anton Hosp, Goch, Germany

[14] Klinikum Ludenscheid, Ludenscheid, Germany

[15] Krankenhaus Barmherzigen Schwestern Linz, Linz, Austria

[16] Krankenhaus Elisabethinen Linz, Linz, Austria

[17] Hannover Med Sch, D-30623 Hannover, Germany

来源：

BLOOD | 2013年 / 121卷 / 23期

关键词：

PROGNOSTIC IMPACT; GENE MUTATION;

D O I：

10.1182/blood-2012-10-461624

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

In this study, we evaluated the frequency and prognostic impact of DNMT3A mutations (DNMT3A(mut)) in 1770 younger adult patients with acute myeloid leukemia (AML) in the context of other genetic alterations and the European LeukemiaNet (ELN) classification. DNMT3A(mut) were found in 20.9% of AMLs and were associated with older age (P < .0001), higher white blood cell counts (P < .0001), cytogenetically normal AML (CN-AML; P < .0001), NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P < .0001), and IDH1/2 mutations (P < .0001). In univariable and multivariable analyses, DNMT3A(mut) did not impact event-free, relapse-free (RFS), or overall survival (OS) in either the entire cohort or in CN-AML; a negative prognostic effect was found only in the ELN unfavorable CN-AML subset (OS, P = .011). In addition, R882 mutations vs non-R882 mutations showed opposite clinical effects-unfavorable for R882 on RFS (all: hazard ratio [HR], 1.29 [P = .026]; CN-AML: HR, 1.38 [P = .018]) and favorable for non-R882 on OS (all: HR, 0.77 [P = .057]; CN-AML: HR, 0.73 [P = .083]). In our statistically high-powered study with minimized selection bias, DNMT3A(mut) represent a frequent genetic lesion in younger adults with AML but have no significant impact on survival end points; only moderate effects on outcome were found, depending on molecular subgroup and DNMT3A(mut) type.

引用

页码：4769 / 4777

页数：9

共 36 条

[31] Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity [J].

Taskesen, Erdogan ;

Bullinger, Lars ;

Corbacioglu, Andrea ;

Sanders, Mathijs A. ;

Erpelinck, Claudia A. J. ;

Wouters, Bas J. ;

van der Poel-van de Luytgaarde, Sonja C. ;

Damm, Frederik ;

Krauter, Juergen ;

Ganser, Arnold ;

Schlenk, Richard F. ;

Lowenberg, Bob ;

Delwel, Ruud ;

Doehner, Hartmut ;

Valk, Peter J. M. ;

Doehner, Konstanze .

BLOOD, 2011, 117 (08) :2469-2475

[32]

Therneau TM, 2000, STAT BIOL HEALTH

[33] Incidence and Prognostic Influence of DNMT3A Mutations in Acute Myeloid Leukemia [J].

Thol, Felicitas ;

Damm, Frederik ;

Luedeking, Andrea ;

Winschel, Claudia ;

Wagner, Katharina ;

Morgan, Michael ;

Yun, Haiyang ;

Goehring, Gudrun ;

Schlegelberger, Brigitte ;

Hoelzer, Dieter ;

Luebbert, Michael ;

Kanz, Lothar ;

Fiedler, Walter ;

Kirchner, Hartmut ;

Heil, Gerhard ;

Krauter, Juergen ;

Ganser, Arnold ;

Heuser, Michael .

JOURNAL OF CLINICAL ONCOLOGY, 2011, 29 (21) :2889-2896

[34] Molecular and Enzymatic Profiles of Mammalian DNA Methyltransferases: Structures and Targets for Drugs [J].

Xu, F. ;

Mao, C. ;

Ding, Y. ;

Rui, C. ;

Wu, L. ;

Shi, A. ;

Zhang, H. ;

Zhang, L. ;

Xu, Z. .

CURRENT MEDICINAL CHEMISTRY, 2010, 17 (33) :4052-4071

[35] Array-based genomic resequencing of human leukemia [J].

Yamashita, Y. ;

Yuan, J. ;

Suetake, I. ;

Suzuki, H. ;

Ishikawa, Y. ;

Choi, Y. L. ;

Ueno, T. ;

Soda, M. ;

Hamada, T. ;

Haruta, H. ;

Takada, S. ;

Miyazaki, Y. ;

Kiyoi, H. ;

Ito, E. ;

Naoe, T. ;

Tomonaga, M. ;

Toyota, M. ;

Tajima, S. ;

Iwama, A. ;

Mano, H. .

ONCOGENE, 2010, 29 (25) :3723-3731

[36] Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia [J].

Yan, Xiao-Jing ;

Xu, Jie ;

Gu, Zhao-Hui ;

Pan, Chun-Ming ;

Lu, Gang ;

Shen, Yang ;

Shi, Jing-Yi ;

Zhu, Yong-Mei ;

Tang, Lin ;

Zhang, Xiao-Wei ;

Liang, Wen-Xue ;

Mi, Jian-Qing ;

Song, Huai-Dong ;

Li, Ke-Qin ;

Chen, Zhu ;

Chen, Sai-Juan .

NATURE GENETICS, 2011, 43 (04) :309-U51

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