Landscape of genetic lesions in 944 patients with myelodysplastic syndromes

被引：1322

作者：

Haferlach, T. ^{[1
]}

Nagata, Y. ^{[2
,4
]}

Grossmann, V. ^{[1
]}

Okuno, Y. ^{[2
]}

Bacher, U. ^{[1
]}

Nagae, G. ^{[3
]}

Schnittger, S. ^{[1
]}

Sanada, M. ^{[2
,4
]}

Kon, A. ^{[2
,4
]}

Alpermann, T. ^{[1
]}

Yoshida, K. ^{[2
,4
]}

Roller, A. ^{[1
]}

Nadarajah, N. ^{[1
]}

Shiraishi, Y. ^{[6
]}

Shiozawa, Y. ^{[2
,4
]}

Chiba, K. ^{[6
]}

Tanaka, H. ^{[5
]}

Koeffler, H. P. ^{[7
,8
]}

Klein, H-U ^{[9
]}

Dugas, M. ^{[9
]}

Aburatani, H. ^{[3
]}

Kohlmann, A. ^{[1
]}

Miyano, S. ^{[5
,6
]}

Haferlach, C. ^{[1
]}

Kern, W. ^{[1
]}

Ogawa, S. ^{[2
,4
]}

机构：

[1] Munich Leukemia Lab, D-81377 Munich, Germany

[2] Univ Tokyo, Grad Sch Med, Canc Genom Project, Tokyo, Japan

[3] Univ Tokyo, Res Ctr Adv Sci & Technol, Genome Sci Div, Tokyo, Japan

[4] Kyoto Univ, Grad Sch Med, Dept Pathol & Tumor Biol, Kyoto, Japan

[5] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab Sequence Data Anal, Tokyo, Japan

[6] Univ Tokyo, Inst Med Sci, Lab DNA Informat Anal, Tokyo, Japan

[7] Cedars Sinai Med Ctr, Dept Hematol Oncol, Los Angeles, CA 90048 USA

[8] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117548, Singapore

[9] Univ Munster, Inst Med Informat, D-48149 Munster, Germany

来源：

LEUKEMIA | 2014年 / 28卷 / 02期

关键词：

next-generation sequencing; molecular markers; myelodysplastic syndromes; prognostic score; PROGNOSTIC SCORING SYSTEM; MUTATIONS; MACHINERY; EVOLUTION; LEUKEMIA; PATHWAY; EZH2;

D O I：

10.1038/leu.2013.336

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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.

引用

页码：241 / 247

页数：7

共 33 条

[1]

Validation of a Prognostic Model and the Impact of Mutations in Patients With Lower-Risk Myelodysplastic Syndromes [J].