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Leukemia. 2014 Aug;28(8):1586-95. doi: 10.1038/leu.2014.55. Epub 2014 Feb 3.

Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients.

Author information

1
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
2
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.
3
Department of Hematology, Kumamoto University School of Medicine, Kumamoto, Japan.
4
Department of Clinical Laboratory Science, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
5
Division of Hematology, Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan.
6
Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
7
Leukemia Research Center, Saiseikai Maebashi Hospital, Maebashi, Japan.
8
Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.
9
Division of Clinical Oncology and Hematology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan.
10
Department of Hematology, Kanagawa Cancer Center, Kanagawa, Japan.
11
Department of Hematology, Tokyo Medical University, Tokyo, Japan.
12
Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan.
13
Department of Hematology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
14
Division of Hematology, Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
15
Division of Hematology, Ichinomiya Municipal Hospital, Ichinomiya, Japan.
16
Department of Hematology, Chiba University Hospital, Chiba, Japan.
17
Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan.
18
Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
19
Division of Hematology, Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
20
Department of Hematology, Kumamoto Shinto General Hospital, Kumamoto, Japan.
21
Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology (DNHMED), Yamagata University School of Medicine, Yamagata, Japan.
22
Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, Nagakute, Japan.
23
Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
24
Laboratory of Sequence Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
25
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.
26
1] Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan [2] National Hospital Organization Nagoya Medical Center, Nagoya, Japan.

Abstract

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.

PMID:
24487413
DOI:
10.1038/leu.2014.55
[Indexed for MEDLINE]

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