Landscape of genetic lesions in 944 patients with myelodysplastic syndromes
By T. Haferlach, Y. Nagata, V. Grossmann, Y. Okuno, U. Bacher, G. Nagae, Susanne Schnittger, M. Sanada, A. Kon, T. Alpermann and 16 more. Leukemia, 2013
1,487 citations recorded by the source corpus.
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.
Subfields: Cancer Research, Genetics, Hematology
View Paper: https://www.semanticscholar.org/paper/b1de62d9d5aebfe53d4bb6c96ab72090f204ac62
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Citations in the corpus
- Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. (2015, neutral): “14 Detection of an MDS-associated mutation can provide additional diagnostic support in cases for which the clinical presentation and morphology are ambiguous.”
- Genomic Classification and Prognosis in Acute Myeloid Leukemia (2016, neutral): “In contrast, the NPM1–DNMT3A–NRASG12/13 genotype carried an unexpectedly benign prognosis in our cohort (P = 0.04 for three-way inter- Pr ob ab ili ty o f S ur vi va l 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 ”
- Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. (2017, background): “1 Genetic basis The related and partially overlapping clinical phenotypes of MDS and AML are reflected in the genetic bases of the two diseases.(31,37,78,79,80,124) A subset of mutations are highly specific”
- The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms (2022, neutral): “Clinical detection of biallelic TP53 alterations is based on sequencing analysis (covering at least exons 4 to 11) [29, 32], often coupled with a technique to detect copy number status, usually fluorescence in situ hybridization with a probe set specific for the TP53 locus on 17p13.”
- Role of TET enzymes in DNA methylation, development, and cancer (2016, background): “Accordingly, with statistical significance, TET2 mutations are associated with SF3B1, ZRSR2, and ASXL1 mutations in MDS patients (Haferlach et al. 2014); STAG2, DNAH9, and serine–threonine kinasemutations inAML patients (CancerGenome Atlas Research Network 2013); and RHOA, IDH2, and DNMT3A mutations”