A geno-clinical decision model for the diagnosis of myelodysplastic syndromes.
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ABSTRACT:
SUBMITTER: Radakovich N
PROVIDER: S-EPMC8579270 | biostudies-literature | 2021 Nov
REPOSITORIES: biostudies-literature
Publications
A geno-clinical decision model for the diagnosis of myelodysplastic syndromes.
Radakovich Nathan N Meggendorfer Manja M Malcovati Luca L Hilton C Beau CB Sekeres Mikkael A MA Shreve Jacob J Rouphail Yazan Y Walter Wencke W Hutter Stephan S Galli Anna A Pozzi Sara S Elena Chiara C Padron Eric E Savona Michael R MR Gerds Aaron T AT Mukherjee Sudipto S Nagata Yasunobu Y Komrokji Rami S RS Jha Babal K BK Haferlach Claudia C Maciejewski Jaroslaw P JP Haferlach Torsten T Nazha Aziz A
Blood advances 20211101 21
The differential diagnosis of myeloid malignancies is challenging and subject to interobserver variability. We used clinical and next-generation sequencing (NGS) data to develop a machine learning model for the diagnosis of myeloid malignancies independent of bone marrow biopsy data based on a 3-institution, international cohort of patients. The model achieves high performance, with model interpretations indicating that it relies on factors similar to those used by clinicians. In addition, we de ...[more]
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Project description:BackgroundMyelodysplastic syndromes (MDS) are malignant stem-cell diseases that are usually diagnosed in elderly patients who present with anemia or, less commonly, bi- or pancytopenia. Their incidence in persons over age 80 is above 50 new cases per 100,000 persons per year. Their clinical course is highly variable. About one-quarter of all patients with MDS develop acute leukemia. The median survival time from the moment of diagnosis is about 30 months.MethodWe selectively searched the PubMed database for pertinent articles and guidelines from the years 2000-2013. We used the search term "myelodysplastic syndromes."ResultsMDS are diagnosed by cytology, with consideration of the degree of dysplasia and the percentage of blast cells in the blood and bone marrow, and on a cytogenetic basis, as recommended in the WHO classification. In particular, chromosomal analysis is necessary for prognostication. The Revised International Prognosis Scoring System (IPSS-R) enables more accurate prediction of the course of disease by dividing patients into a number of low- and high-risk groups. The median survival time ranges from a few months to many years. The approved treatments, aside from transfusion therapy, include iron depletion therapy for low-risk patients, lenalidomide for low-risk patients with a deletion on the long arm of chromosome 5, and 5-azacytidine for high-risk patients. High-risk patients up to age 70 who have no major accompanying illnesses should be offered allogenic stem-cell transplantation with curative intent. The cure rates range from 30% to 50%. Mucositis, hemorrhages, infections, and graft-versus-host diseases are the most common complications of this form of treatment.ConclusionMyelodysplastic syndromes are treated on an individualized, risk-adapted basis after precise diagnostic evaluation and after assessment of the prognosis. More studies are needed so that stage-adapted treatment can be improved still further.
| S-EPMC3855821 | biostudies-literature
Project description:The myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) are a unique group of hematologic malignancies characterized by concomitant myelodysplastic and myeloproliferative features. According to the 2008 WHO classification, the category includes atypical chronic myeloid leukemia (aCML), chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), MDS/MPN-unclassifiable (MDS/MPN-U), and the provisional entity refractory anemia with ring sideroblasts and thrombocytosis (RARS-T). Although diagnosis currently remains based on clinicopathologic features, the incorporation of next-generation platforms has allowed for the recent molecular characterization of these diseases which has revealed unique and complex mutational profiles that support their distinct biology and is anticipated to soon play an integral role in diagnosis, prognostication, and treatment. Future goals of research should include the development of disease-modifying therapies, and further genetic understanding of the category will likely form the foundation of these efforts.
| S-EPMC5069836 | biostudies-other
Project description:Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic neoplasms varying in severity affecting one or more lines of hematopoiesis. Ineffective erythropoiesis results in dysregulation of iron metabolism. Most MDS patients have anemia, and some require regular red blood cell transfusions. These transfusions, in addition to factors of the disease itself, can result in iron overload (IO). Retrospective analyses suggest that MDS patients with IO have reduced overall survival and poorer outcomes following allogeneic stem cell transplant vs. those without IO. Iron chelation therapy (ICT; deferoxamine, deferasirox, or deferiprone) has been used to alleviate IO in other transfusion-dependent hematologic conditions (e.g., thalassemia), but its role in MDS has not been firmly established. A growing body of evidence suggests that ICT in MDS patients is an effective means for reducing transfusional IO and may significantly improve outcomes such as survival. The orally administered iron chelator deferasirox has been widely studied in MDS, and available studies have shown it to be generally well tolerated and effective in reducing IO in this population. The pathophysiology and clinical consequences of IO in MDS, as well as current methods for diagnosing and treating IO in these patients, are discussed.
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Project description:In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P < .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positive predictive value for ring sideroblasts of 97.7% (95% confidence interval, 93.5%-99.5%). In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049). The close association between SF3B1 mutations and disease phenotype with ring sideroblasts across MDS and MDS/MPN is consistent with a causal relationship. Furthermore, SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS.
| S-EPMC3236114 | biostudies-literature
Project description:The myelodysplastic syndromes are a diverse group of clonal stem cell disorders characterized by ineffective hematopoiesis, peripheral cytopenias, and an increased propensity to evolve to acute myeloid leukemia. The molecular pathogenesis of these disorders is poorly understood, but recurring chromosomal abnormalities occur in approximately 50% of cases and are the focus of much investigation. The availability of newer molecular techniques has allowed the identification of additional genetic aberrations, including mutations and epigenetic changes of prognostic and potential therapeutic importance. This review focuses on the key role of cytogenetic analysis in myelodysplastic syndromes in the context of the diagnosis, prognosis, and pathogenesis of these disorders.
| S-EPMC4340482 | biostudies-literature
Project description:BackgroundMyelodysplastic syndromes are clinically heterogeneous disorders characterized by clonal hematopoiesis, impaired differentiation, peripheral-blood cytopenias, and a risk of progression to acute myeloid leukemia. Somatic mutations may influence the clinical phenotype but are not included in current prognostic scoring systems.MethodsWe used a combination of genomic approaches, including next-generation sequencing and mass spectrometry-based genotyping, to identify mutations in samples of bone marrow aspirate from 439 patients with myelodysplastic syndromes. We then examined whether the mutation status for each gene was associated with clinical variables, including specific cytopenias, the proportion of blasts, and overall survival.ResultsWe identified somatic mutations in 18 genes, including two, ETV6 and GNAS, that have not been reported to be mutated in patients with myelodysplastic syndromes. A total of 51% of all patients had at least one point mutation, including 52% of the patients with normal cytogenetics. Mutations in RUNX1, TP53, and NRAS were most strongly associated with severe thrombocytopenia (P<0.001 for all comparisons) and an increased proportion of bone marrow blasts (P<0.006 for all comparisons). In a multivariable Cox regression model, the presence of mutations in five genes retained independent prognostic significance: TP53 (hazard ratio for death from any cause, 2.48; 95% confidence interval [CI], 1.60 to 3.84), EZH2 (hazard ratio, 2.13; 95% CI, 1.36 to 3.33), ETV6 (hazard ratio, 2.04; 95% CI, 1.08 to 3.86), RUNX1 (hazard ratio, 1.47; 95% CI, 1.01 to 2.15), and ASXL1 (hazard ratio, 1.38; 95% CI, 1.00 to 1.89).ConclusionsSomatic point mutations are common in myelodysplastic syndromes and are associated with specific clinical features. Mutations in TP53, EZH2, ETV6, RUNX1, and ASXL1 are predictors of poor overall survival in patients with myelodysplastic syndromes, independently of established risk factors. (Funded by the National Institutes of Health and others.).
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Project description:Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling. We sequenced 111 genes across 738 patients with MDS or closely related neoplasms (including chronic myelomonocytic leukemia and MDS-myeloproliferative neoplasms) to explore the role of acquired mutations in MDS biology and clinical phenotype. Seventy-eight percent of patients had 1 or more oncogenic mutations. We identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers. Coupled with inferences on subclonal mutations, these data suggest a hypothesis of genetic "predestination," in which early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes. Driver mutations had equivalent prognostic significance, whether clonal or subclonal, and leukemia-free survival deteriorated steadily as numbers of driver mutations increased. Thus, analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application.
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Project description:Myelodysplastic syndromes (MDS) are a very heterogeneous disease, with extremely variable clinical features and outcomes. Current management relies on risk stratification based on IPSS and IPSS-R, which categorizes patients into low (LR-) and high-risk (HR-) MDS. Therapeutic strategies in LR-MDS patients mainly consist of erythropoiesis stimulating agents (ESAs), transfusion support, and luspatercept or lenalidomide for selected patients. Current unmet needs include the limited options available after treatment failure, and the consequent transfusion burden with several hospital admissions and poor quality of life. Therapeutic approaches in HR-MDS patients are aimed at changing the natural course of the disease and hypometylating agents (HMA) are the first choice. The only potentially curative treatment is allogeneic stem cell transplant (allo-HCT), restricted to a minority of young and fit candidates. Patients unfit for or those that relapse after the abovementioned options harbor an adverse prognosis, with limited overall survival and frequent leukemic evolution. Recent advances in genetic mutations and intracellular pathways that are relevant for MDS pathogenesis are improving disease risk stratification and highlighting therapeutic targets addressed by novel agents. Several drugs are under evaluation for LR and HR patients, which differ by their mechanism of action, reported efficacy, and phase of development. This review analyzes the current unmet clinical needs for MDS patients and provides a critical overview of the novel agents under development in this setting.
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Project description:TP53 dysregulation plays a pivotal role in the molecular pathogenesis of myelodysplastic syndromes (MDS), identifying a subgroup of patients with peculiar features. In this review we report the recent biological and clinical findings of TP53-mutated MDS, focusing on the molecular pathways activation and on its impact on the cellular physiology. In MDS, TP53 mutational status is deeply associated with del(5q) syndrome and its dysregulation impacts on cell cycle, DNA repair and apoptosis inducing chromosomal instability and the clonal evolution of disease. TP53 defects influence adversely the MDS clinical outcome and the treatment response rate, thus new therapeutic approaches are being developed for these patients. TP53 allelic state characterization and the mutational burden evaluation can therefore predict prognosis and identify the subgroup of patients eligible for targeted therapy. For these reasons, in the era of precision medicine, the MDS diagnostic workup cannot do without the complete assessment of TP53 mutational profile.
| S-EPMC7279310 | biostudies-literature
Project description:AbstractMyelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. Although genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations, and copy-neutral loss of heterozygosity were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91%, 43%, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and loss of heterozygosity at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow (BM) blast percentage across groups ranged from 1.5% to 10%, and the median overall survival ranged from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of BM blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and might inform future classification schemas and translational therapeutic research.
| S-EPMC11487646 | biostudies-literature