Landscape of genetic lesions in 944 patients with myelodysplastic syndromes

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.

Targeted deep sequencing of CD34+ cells from peripheral blood can reproduce bone marrow molecular profile in myelodysplastic syndromes

“…As previously reported we detected an increased number of genetic lesions in high‐risk WHO subtypes (Supporting Information Figure S3A) and found a correlation between the average number of genetic aberrations and the IPSS‐R prognostic risk score (Supporting Information Figure S3B) 1, 2. Interestingly, low risk patients displayed an increased number of somatic mutations compared to the number of lesions detected by CBA or SNP‐A.…”

“…To identify molecular markers of clinical relevance, we screened genes previously reported to be frequently mutated in MDS and other myeloid malignancies 1, 2. The somatic origin of the variants was validated by comparison of the concurrent samples (BMC, PB‐CD34, and PB‐MC) with a paired germline sample, peripheral CD3 + cells (PB‐CD3).…”

Clonal hematopoiesis in acquired aplastic anemia

“…Other MDS/AML-related genes were also recurrently mutated but at lower frequencies ( Figure 3). 18,20,66 The highly recurrent nature of well-characterized driver mutations indicates that they were selected by a Darwinian mechanism, rather than stochastically achieving a clonal dominance merely by a rapid expansion from a small number of residual stem cells ("bottleneck"). 9 In several patients, some of these genes, including PIGA, DNMT3A, ASXL1, BOCR, and RUNX1, harbor multiple, independent mutations, suggesting a strong selective pressure favoring evolution of cells having these mutations ( Figure 3A).…”

Karyotype evolution and acquisition of FLT3 or RAS pathway alterations drive progression of myelodysplastic syndrome to acute myeloid leukemia

“…Previous studies on MDS patients showed that mutations in ASXL1, ETV6, EZH2, IDH2, RUNX1, and TP53 are predictors of poor overall survival in MDS patients independently of other established risk factors. [11][12][13] Furthermore the splicing machinery is one of the most frequently affected pathways in MDS, 14 and mutations in SRSF2 have been shown to be independently associated with a negative prognosis for overall survival and AML transformation. 15 Recently, several of these gene mutations were identified as specific for s-AML in comparison to de novo AML underlining their function in dysplastic differentiation since they occur already at the stage of MDS.…”