Survival differences and associated molecular signatures of DNMT3A-mutant acute myeloid leukemia patients
| Autor: | Lars Bullinger, Nádia C. Correia, Michael Seifert, Andreas Trumpp, Anna Dolnik, Michael A. Rieger, Ingo Roeder, Chris Lauber |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Cellular differentiation DNA Mutational Analysis lcsh:Medicine Kaplan-Meier Estimate Gene mutation DNA Methyltransferase 3A 0302 clinical medicine Cluster Analysis DNA (Cytosine-5-)-Methyltransferases lcsh:Science Oligonucleotide Array Sequence Analysis Clinical Trials as Topic Multidisciplinary Gene Expression Regulation Leukemic Remission Induction Nuclear Proteins Myeloid leukemia Middle Aged Cell cycle Prognosis Up-Regulation Leukemia Myeloid Acute Haematopoiesis Treatment Outcome 030220 oncology & carcinogenesis Nucleophosmin Adult NPM1 Adolescent Biology Article Acute myeloid leukaemia Young Adult 03 medical and health sciences microRNA Humans Data mining Gene Aged Gene Expression Profiling lcsh:R Survival Analysis MicroRNAs 030104 developmental biology fms-Like Tyrosine Kinase 3 Mutation Cancer research lcsh:Q |
| Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-17 (2020) Scientific Reports |
| Popis: | Acute myeloid leukemia (AML) is a very heterogeneous and highly malignant blood cancer. Mutations of the DNA methyltransferase DNMT3A are among the most frequent recurrent genetic lesions in AML. The majority of DNMT3A-mutant AML patients shows fast relapse and poor survival, but also patients with long survival or long-term remission have been reported. Underlying molecular signatures and mechanisms that contribute to these survival differences are only poorly understood and have not been studied in detail so far. We applied hierarchical clustering to somatic gene mutation profiles of 51 DNMT3A-mutant patients from The Cancer Genome Atlas (TCGA) AML cohort revealing two robust patient subgroups with profound differences in survival. We further determined molecular signatures that distinguish both subgroups. Our results suggest that FLT3 and/or NPM1 mutations contribute to survival differences of DNMT3A-mutant patients. We observed an upregulation of genes of the p53, VEGF and DNA replication pathway and a downregulation of genes of the PI3K-Akt pathway in short- compared to long-lived patients. We identified that the majority of measured miRNAs was downregulated in the short-lived group and we found differentially expressed microRNAs between both subgroups that have not been reported for AML so far (miR-153-2, miR-3065, miR-95, miR-6718) suggesting that miRNAs could be important for prognosis. In addition, we learned gene regulatory networks to predict potential major regulators and found several genes and miRNAs with known roles in AML pathogenesis, but also interesting novel candidates involved in the regulation of hematopoiesis, cell cycle, cell differentiation, and immunity that may contribute to the observed survival differences of both subgroups and could therefore be important for prognosis. Moreover, the characteristic gene mutation and expression signatures that distinguished short- from long-lived patients were also predictive for independent DNMT3A-mutant AML patients from other cohorts and could also contribute to further improve the European LeukemiaNet (ELN) prognostic scoring system. Our study represents the first in-depth computational approach to identify molecular factors associated with survival differences of DNMT3A-mutant AML patients and could trigger additional studies to develop robust molecular markers for a better stratification of AML patients with DNMT3A mutations. |
| Databáze: | OpenAIRE |
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