Genetics of Myelodysplastic Syndromes

Saygin, Caner; Godley, Lucy A.

doi:10.3390/cancers13143380

Cited by 12 publications

(12 citation statements)

References 78 publications

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“…Myelodysplastic syndromes (MDS) are one of the most prevalent hematological malignancies originating from hematopoietic stem/progenitor cells. It is a very heterogeneous group of myeloid disorders characterized by somatic mutations in hematopoietic stem cells, leading to ineffective hematopoiesis, bone marrow dysplasia, and an increased risk of transformation to acute leukemia (1).…”

Section: Introductionmentioning

confidence: 99%

Prognostic Impact of Platelet-Large Cell Ratio In Myelodysplastic Syndromes

Chen

Zhang

et al. 2022

Front. Oncol.

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BackgroundMyelodysplastic syndromes (MDSs) are a very heterogeneous group of myeloid disorders with high prevalence and risk of developing acute myeloid leukemia. The more accurate risk stratification can provide a better guidance of treatment. The platelet–large cell ratio (P-LCR) is a parameter reported in complete blood cell count tests, and was associated with many diseases, but its role in MDS is not clear.PurposeThis study aims to explore the impact of the P-LCR on the prognosis of patients with MDS, which is of great significance for clinical treatment.MethodsIn the retrospective study, 122 newly diagnosed MDS patients were enrolled. We used the bioinformatics tool X-tile to define a P-LCR threshold of 36.7% to predict prognosis. Patients were divided into P-LCRlow and P-LCRhigh groups, and their characteristics were compared between the two groups.ResultsResults show that the P-LCRlow was associated with worse overall survival (OS) than the P-LCRhigh patients (median OS, 18.53 months versus 25.77 months, p=0.0057), but there were no statistical differences in progression-free survival (PFS) between the two groups (p=0.2001). The results of univariate and multivariate Cox proportional hazard analyses adjusted for gender, bone marrow blast level, platelet count, and International Prognostic Scoring System scores showed that the P-LCR was useful in the evaluation of PFS [hazard ratio (HR) 0.212, 95%CI 0.064–0.702, p=0.011] and OS of MDS (HR 0.464, 95%CI 0.284–0.757, p=0.002).ConclusionThis study is the first report showing that the P-LCR would be a simple and immediately available biomarker for predicting the prognosis of MDS.

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Section: Introductionmentioning

confidence: 99%

Prognostic Impact of Platelet-Large Cell Ratio In Myelodysplastic Syndromes

Chen

Zhang

et al. 2022

Front. Oncol.

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“…Accumulation of epigenetic modifications together with occurrence of TET2 , IDH1 , and IDH2 gene mutations are proposed as the main driven genetic events favoring MDS transformation to AML 7,29,33 . Most frequent mutations involve SF3B1 , TET2 , ASXL1 , SRSF2 , DNMT3A , RUNX1 , U2AF1 , ZRSR2 , STAG2 , TP53 , EZH2 , CBL , JAK2 , BCOR , IDH2 , NRAS , and NF1 genes, and some of these alterations have prognostic impact, such as SF3B1 mutations associated with the presence of ring sideroblasts and altering spliceosome machinery activities 6,29,31,34 . Overall, MDS show a higher genomic instability, as cytogenetics abnormalities are found in about 50% of patients, while whole exome sequencing can detect recurrent somatic mutations in 80%–90% of cases, usually six per exome in low‐risk MDS and nine in MDS with excess blasts 5 .…”

Section: Discussionmentioning

confidence: 99%

“…5 No recurrent somatic mutations account for majority of cases contributing to MDS genetic and clinical heterogeneity, even though some frequently mutated gene patterns can be recognized in MDS and AML. 6 Moreover, genetic alterations present in MDS are also frequently found in other hematological disorders and in healthy individuals as clonal hematopoiesis is commonly seen with aging. [7][8][9][10] On the other hand, more than 25% of AML cases do not display somatic mutations in any myeloid neoplasm-related genes, 11 therefore, additional pathogenetic mechanisms are required for dysplastic hemopoiesis, such as immune dysregulation.…”

Section: Introductionmentioning

confidence: 99%

Subclones with variants of uncertain clinical significance might contribute to ineffective hemopoiesis and leukemia predisposition

Giudice

Serio

Errichiello

et al. 2023

European J of Haematology

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BackgroundSplicing modifications, genomic instability, and hypomethylation are central mechanisms promoting myelodysplasia and acute myeloid leukemia (AML). In this real‐life retrospective study, to elucidate pathophysiology of clonal hemopoiesis in hematological malignancies, we investigated clinical significance of mutations in leukemia‐related genes of known pathogenetic significance and of variants of uncertain clinical significance (VUS) in a cohort of patients with MDS and AML.MethodsA total of 59 consecutive subjects diagnosed with MDS, 48 with AML, and 17 with clonal cytopenia with unknown significance were screened for somatic mutations in AML‐related genes by next‐generation sequencing.ResultsWe showed that TET2, SETBP1, ASXL1, EZH2, RUNX1, SRSF2, DNMT3A, and IDH1/2 were commonly mutated. MDS patients also showed a high genetic complexity, especially for SETBP1. Moreover, the presence of SETBP1 wild‐type or two or more simultaneous VUS variants identified a subgroup of AML and MDS patients with better outcome, while the presence of single SETBP1 VUS variant was related to a worse prognosis, regardless TET2 mutational status.ConclusionsIn conclusions, we linked both pathogenic and VUS variants in AML‐related genes to clonal hematopoiesis; therefore, we proposed to consider those variants as prognostic markers in leukemia and myelodysplasia. However, further studies in larger prospective cohorts are required to validate our results.

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“…Specific genes involved in epigenetic regulation (TET2, ASXL1, EZH2, DNMT3A, and IDH1/2), RNA splicing (SF3B1, SRSF2, U2AF1, and ZRSR2), DNA damage response (TP53), transcriptional regulation (RUNX1, BCOR, and ETV6), and signal transduction (CBL, NRAS, and JAK2) have been identified in MDS ( 16 , 17 ). More than 90% of patients with MDS harbor somatic myeloid-related mutations ( 18 , 19 ). In this study, four important genes, TP53, ASXL1, EZH2, and ETV6, were selected to construct a nomogram.…”

Section: Discussionmentioning

confidence: 99%

Development and validation of a novel prognosis prediction model for patients with myelodysplastic syndrome

Liang

Feng²,

Guo³

et al. 2022

Front. Oncol.

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BackgroundSomatic mutations are widespread in patients with Myelodysplastic Syndrome (MDS) and are associated with prognosis. However, a practical prognostic model for MDS that incorporates somatic mutations urgently needs to be developed.MethodsA cohort of 201 MDS patients from the Gene Expression Omnibus (GEO) database was used to develop the model, and a single-center cohort of 115 MDS cohorts from Northwest China was used for external validation. Kaplan-Meier analysis was performed to compare the effects of karyotype classifications and gene mutations on the prognosis of MDS patients. Univariate and multivariate Cox regression analyses and Lasso regression were used to screen for key prognostic factors. The shinyapps website was used to create dynamic nomograms with multiple variables. The time-dependent receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA) were used to evaluate the model’s discrimination, accuracy and clinical utility.ResultsSix risk factors (age, bone morrow blast percentage, ETV6, TP53, EZH2, and ASXL1) were considered as predictor variables in the nomogram. The nomogram showed excellent discrimination, with respective the area under the ROC curve (AUC) values of 0.850, 0.839, 0.933 for the training cohort at 1 year, 3 years and 5 years; 0.715, 0.802 and 0.750 for the testing cohort at 1 year, 3 years and 5 years; and 0.668, 0.646 and 0.731 for the external validation cohort at 1 year, 3 years and 5 years. The calibration curves and decision curve showed that the nomogram had good consistency and clinical practical benefit. Finally, a stratified analysis showed that MDS patients with high risk had worse survival outcomes than patients with low risk.ConclusionWe developed a nomogram containing six risk factors, which provides reliable and objective predictions of prognosis for MDS patients.

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Genetics of Myelodysplastic Syndromes

Cited by 12 publications

References 78 publications

Prognostic Impact of Platelet-Large Cell Ratio In Myelodysplastic Syndromes

Prognostic Impact of Platelet-Large Cell Ratio In Myelodysplastic Syndromes

Subclones with variants of uncertain clinical significance might contribute to ineffective hemopoiesis and leukemia predisposition

Development and validation of a novel prognosis prediction model for patients with myelodysplastic syndrome

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