Landscape of genetic lesions in 944 patients with myelodysplastic syndromes.
High-throughput DNA sequencing significantly contributed to diagnosis and prognostication in patients with myelodysplastic syndromes (MDS). We determined the biological and prognostic significance of genetic aberrations in MDS. In total, 944 patients with various MDS subtypes were screened for known/putative mutations/deletions in 104 genes using targeted deep sequencing and array-based genomic hybridization. In total, 845/944 patients (89.5%) harbored at least one mutation (median, 3 per patient; range, 0-12). Forty-seven genes were significantly mutated with TET2, SF3B1, ASXL1, SRSF2, DNMT3A, and RUNX1 mutated in >10% of cases. Many mutations were associated with higher risk groups and/or blast elevation. Survival was investigated in 875 patients. By univariate analysis, 25/48 genes (resulting from 47 genes tested significantly plus PRPF8) affected survival (P<0.05). The status of 14 genes combined with conventional factors revealed a novel prognostic model ('Model-1') separating patients into four risk groups ('low', 'intermediate', 'high', 'very high risk') with 3-year survival of 95.2, 69.3, 32.8, and 5.3% (P<0.001). Subsequently, a 'gene-only model' ('Model-2') was constructed based on 14 genes also yielding four significant risk groups (P<0.001). Both models were reproducible in the validation cohort (n=175 patients; P<0.001 each). Thus, large-scale genetic and molecular profiling of multiple target genes is invaluable for subclassification and prognostication in MDS patients.
Munich Leukemia Laboratory (MLL), Munich, Germany.
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Haferlach
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.
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Nagata
Munich Leukemia Laboratory (MLL), Munich, Germany.
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Grossmann
Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
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Y
Okuno
Munich Leukemia Laboratory (MLL), Munich, Germany.
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Bacher
Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
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Nagae
Munich Leukemia Laboratory (MLL), Munich, Germany.
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Schnittger
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.
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Sanada
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.
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Kon
Munich Leukemia Laboratory (MLL), Munich, Germany.
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Alpermann
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.
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Yoshida
Munich Leukemia Laboratory (MLL), Munich, Germany.
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A
Roller
Munich Leukemia Laboratory (MLL), Munich, Germany.
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Nadarajah
Laboratory of DNA Information Analysis, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
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Y
Shiraishi
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.
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Y
Shiozawa
Laboratory of DNA Information Analysis, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
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Chiba
Laboratory of Sequence Data Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
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Tanaka
1] Department of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA [2] Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
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Koeffler
Institute of Medical Informatics, University of Münster, Münster, Germany.
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Klein
Institute of Medical Informatics, University of Münster, Münster, Germany.
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M
Dugas
Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
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H
Aburatani
Munich Leukemia Laboratory (MLL), Munich, Germany.
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Kohlmann
1] Laboratory of Sequence Data Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan [2] Laboratory of DNA Information Analysis, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
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Miyano
Munich Leukemia Laboratory (MLL), Munich, Germany.
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Haferlach
Munich Leukemia Laboratory (MLL), Munich, Germany.
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Kern
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.
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Ogawa
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005819:Genetic Markers; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D055815:Young Adult
D005819:Genetic Markers