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Nat Genet. 2017 Feb;49(2):204-212. doi: 10.1038/ng.3742. Epub 2016 Dec 19.

Dynamics of clonal evolution in myelodysplastic syndromes.

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Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Department of Pathology and Tumor Biology, Kyoto University, Kyoto, and Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Leukemia Program, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
MLL Munich Leukemia Laboratory, Munich, Germany.
Clinical Research Center, Nagoya Medical Center, Nagoya, Japan.
Department of Electrical Engineering and Computer Science, Case Western Reserve University, Cleveland, Ohio, USA.
Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Division of Hematology, Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan.
Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Division of Hematology-Oncology, Chang Gung Memorial Hospital-Linkou, Chang Gung University, Taoyuan, Taiwan.


To elucidate differential roles of mutations in myelodysplastic syndromes (MDS), we investigated clonal dynamics using whole-exome and/or targeted sequencing of 699 patients, of whom 122 were analyzed longitudinally. Including the results from previous reports, we assessed a total of 2,250 patients for mutational enrichment patterns. During progression, the number of mutations, their diversity and clone sizes increased, with alterations frequently present in dominant clones with or without their sweeping previous clones. Enriched in secondary acute myeloid leukemia (sAML; in comparison to high-risk MDS), FLT3, PTPN11, WT1, IDH1, NPM1, IDH2 and NRAS mutations (type 1) tended to be newly acquired, and were associated with faster sAML progression and a shorter overall survival time. Significantly enriched in high-risk MDS (in comparison to low-risk MDS), TP53, GATA2, KRAS, RUNX1, STAG2, ASXL1, ZRSR2 and TET2 mutations (type 2) had a weaker impact on sAML progression and overall survival than type-1 mutations. The distinct roles of type-1 and type-2 mutations suggest their potential utility in disease monitoring.

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