Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients.
To clarify the cooperative roles of recurrently identified mutations and to establish a more precise risk classification system in acute myeloid leukemia (AML), we comprehensively analyzed mutations in 51 genes, as well as cytogenetics and 11 chimeric transcripts, in 197 adult patients with de novo AML who were registered in the Japan Adult Leukemia Study Group AML201 study. We identified a total of 505 mutations in 44 genes, while only five genes, FLT3, NPM1, CEBPA, DNMT3A and KIT, were mutated in more than 10% of the patients. Although several cooperative and exclusive mutation patterns were observed, the accumulated mutation number was higher in cytogenetically normal AML and lower in AML with RUNX1-RUNX1T1 and CBFB-MYH11, indicating a strong potential of these translocations for the initiation of AML. Furthermore, we evaluated the prognostic impacts of each sole mutation and the combinations of mutations and/or cytogenetics, and demonstrated that AML patients could be clearly stratified into five risk groups for overall survival by including the mutation status of DNMT3A, MLL-PTD and TP53 genes in the risk classification system of the European LeukemiaNet. These results indicate that the prognosis of AML could be stratified by the major mutation status in combination with cytogenetics.
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
R
R
Kihara
1] Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan [2] Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Y
Y
Nagata
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
H
H
Kiyoi
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
T
T
Kato
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
E
E
Yamamoto
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
K
K
Suzuki
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
F
F
Chen
Department of Hematology, Kumamoto University School of Medicine, Kumamoto, Japan.
N
N
Asou
Department of Clinical Laboratory Science, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
S
S
Ohtake
Division of Hematology, Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan.
S
S
Miyawaki
Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Y
Y
Miyazaki
Leukemia Research Center, Saiseikai Maebashi Hospital, Maebashi, Japan.
T
T
Sakura
Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.
Y
Y
Ozawa
Division of Clinical Oncology and Hematology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan.
N
N
Usui
Department of Hematology, Kanagawa Cancer Center, Kanagawa, Japan.
H
H
Kanamori
Department of Hematology, Tokyo Medical University, Tokyo, Japan.
T
T
Kiguchi
Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan.
K
K
Imai
Department of Hematology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
N
N
Uike
Division of Hematology, Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
F
F
Kimura
Division of Hematology, Ichinomiya Municipal Hospital, Ichinomiya, Japan.
K
K
Kitamura
Department of Hematology, Chiba University Hospital, Chiba, Japan.
C
C
Nakaseko
Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan.
M
M
Onizuka
Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
A
A
Takeshita
Division of Hematology, Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
F
F
Ishida
Department of Hematology, Kumamoto Shinto General Hospital, Kumamoto, Japan.
H
H
Suzushima
Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology (DNHMED), Yamagata University School of Medicine, Yamagata, Japan.
Y
Y
Kato
Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, Nagakute, Japan.
H
H
Miwa
Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Y
Y
Shiraishi
Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
K
K
Chiba
Laboratory of Sequence Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
H
H
Tanaka
1] Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan [2] Laboratory of Sequence Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
S
S
Miyano
1] Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan [2] Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
S
S
Ogawa
1] Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan [2] National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
T
T
Naoe
D000293:Adolescent; D000328:Adult; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D003582:Cytogenetics; D018572:Disease-Free Survival; D006801:Humans; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D000090243:Nucleophosmin; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D019009:Proto-Oncogene Proteins c-kit; D051941:fms-Like Tyrosine Kinase 3