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Dynamics of clonal evolution in myelodysplastic syndromes

Abstract

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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Figure 1: Numbers, allele frequency and diversity of somatic nonsynonymous mutations.
Figure 2: Clonal evolution from MDS to sAML analyzed by WES.
Figure 3: Dynamics of major driver mutations revealed by targeted sequencing.
Figure 4: Distinct sets of driver mutations in MDS and their impact on clinical outcomes.
Figure 5: Effects of clone size of driver mutations on prognosis.
Figure 6: Combination of type-1 and type-2 mutations in MDS.

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Acknowledgements

This work was supported by US National Institutes of Health (NIH) grants RO1HL-082983 (J.P.M.), U54 RR019391 (J.P.M.) and K24 HL-077522 (J.P.M.), a grant from the AA & MDS International Foundation (J.P.M., M.A.S. and H.M.), the Robert Duggan Charitable Fund (J.P.M.), a grant from Edward P. Evans Foundation (J.P.M. and M.A.S.), Scott Hamilton CARES grant (H.M.), Grant-in-Aids from the Ministry of Health, Labor and Welfare of Japan, the Japanese Agency for Medical Research and Development (Health and Labour Sciences Research Expenses for Commission and Applied Research for Innovative Treatment of Cancer) and KAKENHI (26221308, 23249052, 22134006, 15H05909, hp160219 and 21790907; S.O.), (15km0305018h0101, 16H05338; H.M.), (26890016; K.Y.), project for development of innovative research on cancer therapies (FIRST, p-direct; S.O.), the Japan Society for the Promotion of Science (JSPS) through the 'Funding Program for World-Leading Innovative R&D on Science and Technology', initiated by the Council for Science and Technology Policy (CSTP) (S.O.), NHRI-EX100-10003NI Taiwan (L.-Y.S.), National Aeronautics and Space Administration grant NNJ13ZSA001N (T.R.), and a grant from the American Cancer Society (Research Scholar Grant 123436-RSG-12-159-01-DMC, to T.L.). Supercomputing resources were also provided by the Human Genome Center, the Institute of Medical Science, The University of Tokyo.

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H.M.: project leader, analysis coordination, variant validation production and manuscript preparation. T.Y.: project leader, sequence analysis, microarray data analysis and manuscript preparation. K.Y.: data analysis team and variant validation production. M.A.S.: clinical data and specimen acquisition and manuscript preparation. T.R.: data analysis, manuscript preparation. H.S.: data analysis team and variant validation production. B.P.: supervisor data analysis team and variant validation production. Y.N.: hybridization-based capture next-generation platform development. M.M.: clinical data and specimen acquisition, data analysis. M.S.: sequence analysis. Y.O.: auto-analysis and manuscript preparation. C. Hirsch: clinical data and specimen acquisition, data analysis. T.K.: clinical data and specimen acquisition, data analysis. Y. Sato: microarray data analysis. A.S.-O.: data management, data analysis. T.L.: data analysis and manuscript preparation. N.H.: variant validation production. Y. Shiraishi: data management, data analysis. K.C.: data management, data analysis. C. Haferlach: clinical data and specimen acquisition, data analysis. W.K.: clinical data and specimen acquisition, data analysis. H.T.: data management, data analysis. Y. Shiozawa: data analysis. I.G.-S.: clinical data management. H.D.H.: clinical data management. S.T.: clinical data management. K.M.G.: specimen acquisition. B.D.: specimen acquisition. T.N.: clinical data management and specimen acquisition. S. Miyawaki: clinical data management and specimen acquisition. Y. Saunthararajah: clinical data management and specimen acquisition. S.C.: clinical data management and specimen acquisition. S. Miyano: data management, data analysis automation leader. L.-Y.S.: clinical data and specimen acquisition, study design. T.H.: clinical data and specimen acquisition, study design. S.O. and J.P.M.: project leaders, study design, execution and analysis, manuscript preparation.

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Correspondence to Seishi Ogawa or Jaroslaw P Maciejewski.

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Supplementary Figures 1–19 and Supplementary Tables 1–7. (PDF 13467 kb)

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Makishima, H., Yoshizato, T., Yoshida, K. et al. Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet 49, 204–212 (2017). https://doi.org/10.1038/ng.3742

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