A genetic development route analysis on MDS subset carrying initial epigenetic gene mutations

Xiao, Li; Xu, Feng; Wu, Lingyun; Zhao, Yuwu; Guo, Juan; He, Qi; Zhang, Zheng; Chang, Chen; Wu, Dong

doi:10.1038/s41598-019-55540-w

Cited by 13 publications

(13 citation statements)

References 28 publications

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“…3) shows that the primary mutations mostly developed in DICER1, TP53, and ASXL1 among the examined samples. It is in compliance with the well-known fact that ASXL1 gene is frequently affected primarily in patients with MDS [23]. A clonal evolution path with TP53 as a driver mutation was also described [24].…”

Section: Discussionsupporting

confidence: 64%

“…However, we have identified inconsistencies of such tendency: mutations in genes of microRNA processing (DICER1, DROSHA) appeared in the same clusters. Additionally, it is true for genes of epigenetic regulation (TET2, ASXL1, EZH2, DNMT3A, and IDH1), that was also observed in another research [23]. Such distinguishing tendencies might be related to the interdependent participation of these genes in the same biological pathway.…”

Section: Discussionmentioning

confidence: 53%

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Building and evaluation of bioinformatic pipeline for determination of clonal profiles in myelodysplastic syndrome

Bug

Prikhodko

Bakin

et al. 2020

ICS

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Introduction: There is growing evidence of a connection between tumor clonal profile and its clinical impact. However, there is a lack of a feasible and reliable method for clonal profiling in actual clinical practice. Myelodysplastic syndrome is a clonal hematopoietic stem cell disorder characterized by morphological dysplasia, cytopenia and a high risk of evolution to acute myeloid leukemia. The clinical outcome of myelodysplastic syndrome is greatly heterogeneous; therefore, specific examination of clonal profiles is needed to resolve the prognosis of patients with such complex disorders. Purpose: Development of a pipeline specifically for determining the clonal profiles in patients with myelodysplastic syndrome on the basis of target next-generation sequencing data. Results: The pipeline was developed and evaluated on a set of 35 patients with high-risk myelodysplastic syndrome. It is possible to use the target sequencing data in order to assess the heterogeneity of clonal profiles and characterize their genetic features. This approach allows you to identify the consistency between a specific individual profile and the disease prognosis, which can be critical for the treatment decision. Herein, the characterization and analysis of clonal profiles are presented. Practical relevance: The information about relation patterns between clonal profile characteristics (number of subclones, mutations-per-clone rate) and clinical outcome can be used by doctors in current practice for a more accurate therapy selection depending on the identified individual specificity of the disease.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 53%

Building and evaluation of bioinformatic pipeline for determination of clonal profiles in myelodysplastic syndrome

Bug

Prikhodko

Bakin

et al. 2020

ICS

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“…Li et al 18 showed that the clonal patterns with initial mutations ( ASXL1 , DNMT3A and TET2 ) promoted the occurrence of MDS, while the some additional driver mutations ( SF3B1 , U2AF1 or RUNX1 ) played roles to keep the basic disease features, or give rise to different phenotypes ( BCOR , EZH2 or TP53 ) in individual patients. These mutations were identified as last events for MDS development to be AML.…”

Section: Discussionmentioning

confidence: 99%

“…Gradual accumulation of mutant genes can promote the occurrence and progress of MDS. Therefore, the prognosis of MDS may be related to the accumulation of different co-mutation gene combinations 18 . In this study, gene mutation detection by NGS and related clinical data from 234 MDS patients had been analyzed to explore U2AF1 mutation sites, mutation load and co-mutation genes of MDS and its clinical significance.…”

Section: Introductionmentioning

confidence: 99%

Differential U2AF1 mutation sites, burden and co-mutation genes can predict prognosis in patients with myelodysplastic syndrome

Wang

Guo

Dong

et al. 2020

Sci Rep

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To investigate the U2AF1 gene mutation site, mutation load and co-mutations genes in patients with myelodysplastic syndrome (MDS) and their effects on prognosis. Gene mutation detection by next-generation sequence and related clinical data of 234 MDS patients were retrospectively collected and analyzed for the relationship between the clinical characteristics, treatment efficacy and prognosis of U2AF1 gene mutation. Among the 234 MDS patients, the U2AF1 gene mutation rate was 21.7% (51 cases), and the median variant allele frequency was 39.5%. Compared with the wild type, the U2AF1 mutant had a higher incidence of chromosome 8 aberration, and was positively correlated with the occurrence of ASXL1, RUNX1, SETBP1 gene mutation, negatively correlated with SF3B1, NPM1 genes mutation (p < 0.05). The most common mutation site of U2AF1 was S34F (32 cases), while U2AF1 Q157P site mutations had a higher incidence of chromosome 7 abnormalities (p = 0.003). The U2AF1 gene mutation more frequently coincided with signal pathway related gene mutations (p = 0.043) with a trend of shortened overall survival. Among patients with U2AF1 gene mutations, those with ASXL1 mutations were prone to develop into acute myeloid leukemia, those with RUNX1 mutations had an increased risk of relapse, and those with TET2 mutations had higher 1-year survival rate. Compared with the patient group of lower mutation load (VAF ≤ 40%), the group with higher mutation load of U2AF1 (VAF > 40%) had a significantly lower 1-year survival rate (46.1% and 80.5%, p = 0.027). The criteria of U2AF1 VAF > 40% is an independent indicator for poor prognosis of MDS patients. VAF > 40% of U2AF1 is an independent factor of short OS in MDS patients. MDS patients with a mutation in the Q157P site of U2AF1 and a higher U2AF1 mutation load suggests poor prognosis, and co-mutated genes in U2AF1 can affect disease progression and prognosis.

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“…First, there is often an obvious pre-AML stage, where somatic gene mutations result in initial events (clonal hematopoiesis) and/or driver events (development of MDS phenotypes), largely involving epigenetic regulation, RNA splicing, fewer transcription, and others [7,8]. Second, despite preliminary findings on the roles of late-stage gene mutations involving various signaling pathways or transcription during sAML development [9,10], including our primary consideration on sAML-related mutations [11], the transformation biology of sAML is still not fully understood. There are many unanswered questions, as: Could early or late somatic mutations solely involved in epigenetic regulation or RNA splicing also induce sAML?…”

mentioning

confidence: 99%

Somatic mutations of activated signaling genes, transcription factors, or tumor suppressors are a precondition for leukemic transformation from myelodysplastic syndromes: a sequencing analysis of 64 paired samples

Chang

et al. 2021

Preprint

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The transformation biology of secondary AML from MDS is still not fully understood. Here, we performed a large cohort of paired sequences including target, whole-exome and single cell sequencing to search AML transformation- related mutations (TRM). The results showed that fifty-five out of the 64 (85.9%) patients presented presumptive TRM involving activated signaling, transcription factors, or tumor suppressors. Most of TRM (63.6%, 35 cases) emerged at the leukemia transformation point. All five of the remaining nine patients analyzed by paired whole exome sequencing showed TRM which are not included in the reference targets. Single-cell sequencing indicated that the activated cell signaling route was related to TRM which take place prior to phenotypic development. Of note, defined TRM was limited to a small set of genes (less than ten, in the order: NRAS/KRAS, CEBPA, TP53, FLT3, RUNX1, CBL, PTPN11 and WT1, accounted for 91.0% of the mutations). In conclusion, somatic mutations involving in activated signaling, transcription factors, or tumor suppressors appeared to be a precondition for AML transformation from myelodysplastic syndromes. The TRM may be considered as new therapy targets.

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A genetic development route analysis on MDS subset carrying initial epigenetic gene mutations

Abstract: A total of 563 cases with a diagnosis of MDS (313 with normal karyotypes, 250 with abnormal chromosomes) were subjected to target sequencing (the general data for these cases can be found in Supplementary Table 1). Those with initial mutations were the focus of our study.

Cited by 13 publications

References 28 publications

Building and evaluation of bioinformatic pipeline for determination of clonal profiles in myelodysplastic syndrome

Building and evaluation of bioinformatic pipeline for determination of clonal profiles in myelodysplastic syndrome

Differential U2AF1 mutation sites, burden and co-mutation genes can predict prognosis in patients with myelodysplastic syndrome

Somatic mutations of activated signaling genes, transcription factors, or tumor suppressors are a precondition for leukemic transformation from myelodysplastic syndromes: a sequencing analysis of 64 paired samples

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