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Updated: May 6, 2026
Use of Hematopoietic Stem Cell Transplantation to Assess the Origin of Myelodysplastic Syndrome
Published on: October 3, 2018
Landscape of genetic lesions in 944 patients with myelodysplastic syndromes
T Haferlach1, Y Nagata2, V Grossmann1
1Munich Leukemia Laboratory (MLL), Munich, Germany.
Abstract:
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.
Insights
High-throughput sequencing reveals genetic mutations in most myelodysplastic syndromes (MDS) patients. These genetic profiles create new models to accurately predict patient risk and survival outcomes.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell disorders.
- Accurate prognostication is crucial for guiding treatment decisions in MDS.
- Genetic aberrations play a significant role in MDS pathogenesis and progression.
Purpose of the Study:
- To determine the biological and prognostic significance of genetic aberrations in MDS.
- To identify key genes and mutations associated with MDS subtypes and outcomes.
- To develop novel prognostic models for MDS patients based on genetic profiling.
Main Methods:
- Targeted deep sequencing and array-based genomic hybridization were used to screen 104 genes in 944 MDS patients.
- Mutational status and copy number variations were analyzed.
- Survival analysis was performed on 875 patients to identify prognostic markers.
Main Results:
- 89.5% of patients (845/944) had at least one mutation, with a median of 3 mutations per patient.
- Seventy-two genes were significantly mutated, including TET2, SF3B1, ASXL1, SRSF2, DNMT3A, and RUNX1 (>10% frequency).
- A novel prognostic model (Model-1) integrating 14 key genes and conventional factors stratified patients into four risk groups with distinct survival rates (3-year survival: 95.2% to 5.3%).
- A gene-only model (Model-2) based on the same 14 genes also demonstrated significant risk stratification and was validated in an independent cohort.
Conclusions:
- Large-scale genetic profiling of multiple target genes is invaluable for subclassification and prognostication in MDS.
- The identified genetic aberrations and developed models provide a more precise approach to risk stratification in MDS.
- These findings can aid in personalized treatment strategies and improve patient management for myelodysplastic syndromes.
