Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia.
The clinical and prognostic relevance of many recently identified driver gene mutations in adult acute myeloid leukemia (AML) is poorly defined. We sequenced the coding regions or hotspot areas of 68 recurrently mutated genes in a cohort of 664 patients aged 18 to 86 years treated on 2 phase 3 trials of the German AML Cooperative Group (AMLCG). The median number of 4 mutations per patient varied according to cytogenetic subgroup, age, and history of previous hematologic disorder or antineoplastic therapy. We found patterns of significantly comutated driver genes suggesting functional synergism. Conversely, we identified 8 virtually nonoverlapping patient subgroups, jointly comprising 78% of AML patients, that are defined by mutually exclusive genetic alterations. These subgroups, likely representing distinct underlying pathways of leukemogenesis, show widely divergent outcomes. Furthermore, we provide detailed information on associations between gene mutations, clinical patient characteristics, and therapeutic outcomes in this large cohort of uniformly treated AML patients. In multivariate analyses including a comprehensive set of molecular and clinical variables, we identified DNMT3A and RUNX1 mutations as important predictors of shorter overall survival (OS) in AML patients <60 years, and particularly in those with intermediate-risk cytogenetics. NPM1 mutations in the absence of FLT3-ITD, mutated TP53, and biallelic CEBPA mutations were identified as important molecular prognosticators of OS irrespective of patient age. In summary, our study provides a comprehensive overview of the spectrum, clinical associations, and prognostic relevance of recurrent driver gene mutations in a large cohort representing a broad spectrum and age range of intensively treated AML patients.
Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilans-Universität, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany;
Klaus H
0000-0003-3920-7490
KH
Metzeler
Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilans-Universität, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany;
Tobias
0000-0002-9615-9432
T
Herold
Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilans-Universität, Munich, Germany;
Maja
M
Rothenberg-Thurley
Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany;
Susanne
S
Amler
Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany;
Maria C
MC
Sauerland
Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany;
Dennis
D
Görlich
Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilans-Universität, Munich, Germany;
Stephanie
S
Schneider
Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilans-Universität, Munich, Germany;
Nikola P
NP
Konstandin
Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilans-Universität, Munich, Germany;
Annika
A
Dufour
Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilans-Universität, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany;
Kathrin
K
Bräundl
Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilans-Universität, Munich, Germany;
Bianka
B
Ksienzyk
Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilans-Universität, Munich, Germany;
Evelyn
E
Zellmeier
Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilans-Universität, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany;
Luise
L
Hartmann
Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilans-Universität, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany;
Philipp A
PA
Greif
Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilans-Universität, Munich, Germany;
Michael
M
Fiegl
Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilans-Universität, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany;
Marion
M
Subklewe
Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand;
Stefan K
SK
Bohlander
Department of Internal Medicine 3, Klinikum Leverkusen, Leverkusen, Germany;
Utz
U
Krug
Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany;
Andreas
A
Faldum
Department of Medicine A, Hematology and Oncology, University of Münster, Münster, Germany;
Wolfgang E
WE
Berdel
Department of Medicine, Hematology, Oncology, Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany; and.
Bernhard
B
Wörmann
Department of Medicine A, Hematology and Oncology, University of Münster, Münster, Germany;
Thomas
T
Büchner
Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilans-Universität, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany;
Wolfgang
W
Hiddemann
Department of Oncology and Hematology, Hospital Barmherzige Brüder, Regensburg, Germany.
Jan
J
Braess
Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilans-Universität, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany;
Karsten
0000-0002-5139-4957
K
Spiekermann
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D020732:Cytogenetic Analysis; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics*; D000090243:Nucleophosmin; D011379:Prognosis; D012307:Risk Factors; D016019:Survival Analysis; D055815:Young Adult