Open AccessDynamics of clonal evolution in myelodysplastic syndromes
Author(s) -
Hideki Makishima,
Tetsuichi Yoshizato,
Kenichi Yoshida,
Mikkael A. Sekeres,
Tomas Radivoyevitch,
Hiromichi Suzuki,
B. Przychodzen,
Yasunobu Nagata,
Manja Meggendorfer,
Masashi Sanada,
Yusuke Okuno,
Cassandra M. Hirsch,
Teodora Kuzmanovic,
Yusuke Sato,
Aiko SatoOtsubo,
Thomas LaFramboise,
Naoko Hosono,
Yuichi Shiraishi,
Kenichi Chiba,
Claudia Haferlach,
Wolfgang Kern,
Hiroko Tanaka,
Yusuke Shiozawa,
Inés Gómez-Seguí,
Holleh Husseinzadeh,
Swapna Thota,
Kathryn Guinta,
Brittney Dienes,
Tsuyoshi Nakamaki,
Shuichi Miyawaki,
Yogen Saunthararajah,
Shigeru Chiba,
Satoru Miyano,
Lee Yung Shih,
Torsten Haferlach,
Seishi Ogawa,
Jaroslaw P. Maciejewski
Publication year - 2016
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/ng.3742
Subject(s) - biology , myelodysplastic syndromes , somatic evolution in cancer , neuroblastoma ras viral oncogene homolog , exome sequencing , kras , myeloid leukemia , runx1 , genetics , npm1 , chronic myelomonocytic leukemia , myeloid , cancer research , ptpn11 , mutation , cancer , gene , immunology , bone marrow , karyotype , chromosome , transcription factor
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.