Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 23, Pages 8589-8594Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1407688111
Keywords
prognostic stratification; clonal evolution; gene mutation pattern
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Funding
- Chinese National Key Basic Research Project 973 [2013CB966800]
- National High Tech Program for Biotechnology [863 2012AA02A505]
- Ministry of Health [201202003]
- Mega-projects of Scientific Research for the 12th Five-Year Plan [2013ZX09303302]
- State Key Laboratories Project of Excellence [81123005]
- Samuel Waxman Cancer Research Foundation Co-Principal Investigator Program
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Myelodysplastic syndrome (MDS) includes a group of diseases characterized by dysplasia of bone marrow myeloid lineages with ineffective hematopoiesis and frequent evolution to acute myeloid leukemia (AML). Whole-genome sequencing was performed in CD34(+) hematopoietic stem/progenitor cells (HSPCs) from eight cases of refractory anemia with excess blasts (RAEB), the high-risk subtype of MDS. The nucleotide substitution patterns were found similar to those reported in AML, and mutations of 96 protein-coding genes were identified. Clonal architecture analysis revealed the presence of subclones in six of eight cases, whereas mutation detection of CD34(+) versus CD34(-) cells revealed heterogeneity of HSPC expansion status. With 39 marker genes belonging to eight functional categories, mutations were analyzed in 196 MDS cases including mostly RAEB (n = 89) and refractory cytopenia with multilineage dysplasia (RCMD) (n = 95). At least one gene mutation was detected in 91.0% of RAEB, contrary to that in RCMD (55.8%), suggesting a higher mutational burden in the former group. Gene abnormality patterns differed between MDS and AML, with mutations of activated signaling molecules and NPM1 being rare, whereas those of spliceosome more common, in MDS. Finally, gene mutation profiles also bore prognostic value in terms of overall survival and progression free survival.
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