Risk of disease progression in low-risk MDS is linked to distinct epigenetic subtypes.
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ABSTRACT:
SUBMITTER: Qin T
PROVIDER: S-EPMC6842085 | biostudies-literature | 2019 Nov
REPOSITORIES: biostudies-literature
Publications
Risk of disease progression in low-risk MDS is linked to distinct epigenetic subtypes.
Qin Tingting T Sotzen Jason J Rampal Raajit K RK Rapaport Franck T FT Levine Ross L RL Klimek Virginia V Nimer Stephen D SD Figueroa Maria E ME
Leukemia 20190722 11
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Project description:Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders characterized variably by the presence of peripheral cytopenias, bone marrow hypercellularity and dysplastic changes in the bone marrow. While MDS patients have an increased risk of progression to acute myeloid leukemia (AML), most MDS patients actually succumb to progressive bone marrow failure. Amongst patients classified as low-risk MDS, different clinical evolutions have been observed, with some patients remaining relatively stable for long periods of time (herein, stable MDS), while others show more progressive disease, with worsening cytopenias, and often increased transfusion requirements (herein, progressive MDS). Current risk stratification strategies fail to distinguish these two groups at diagnosis. We report here that these distinct behaviors are encoded at the epigenetic level and that examining DNA methylation profiles of low-risk MDS patients captures underlying differences between the two different groups. In this study, we identified 356 differentially methylated regions (DMRs) between stable and progressive low-risk MDS at the time of diagnosis. The number of DMRs was almost doubled at the time of progression (681 follow-up DMRs), and this was accompanied by an increase in the local variability at specific methylation regions, and an increase in heterogeneity over time. These findings reveal previously unrecognized epigenetic heterogeneity in low-risk MDS patients and opens the possibility for using epigenetic differences to help improve risk-stratification at diagnosis.
2020-04-14 | GSE108247 | GEO
Project description:Distinct Epigenetic Subtypes Are Linked to Disease Progression in Low-Risk MDS
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Project description:ObjectiveTo examine specific symptom progression patterns and possible disease staging in Parkinson disease clinical subtypes.MethodsWe recently identified Parkinson disease clinical subtypes based on comprehensive behavioral evaluations, "Motor Only," "Psychiatric & Motor," and "Cognitive & Motor," which differed in dementia and mortality rates. Parkinson disease participants ("Motor Only": n = 61, "Psychiatric & Motor": n = 17, "Cognitive & Motor": n = 70) and controls (n = 55) completed longitudinal, comprehensive motor, cognitive, and psychiatric evaluations (average follow-up = 4.6 years). Hierarchical linear modeling examined group differences in symptom progression. A three-way interaction among time, group, and symptom duration (or baseline age, separately) was incorporated to examine disease stages.ResultsAll three subtypes increased in motor dysfunction compared to controls. The "Motor Only" subtype did not show significant cognitive or psychiatric changes compared to the other two subtypes. The "Cognitive & Motor" subtype's cognitive dysfunction at baseline further declined compared to the other two subtypes, while also increasing in psychiatric symptoms. The "Psychiatric & Motor" subtype's elevated psychiatric symptoms at baseline remained steady or improved over time, with mild, steady decline in cognition. The pattern of behavioral changes and analyses for disease staging yielded no evidence for sequential disease stages.InterpretationParkinson disease clinical subtypes progress in clear, temporally distinct patterns from one another, particularly in cognitive and psychiatric features. This highlights the importance of comprehensive clinical examinations as the order of symptom presentation impacts clinical prognosis.
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Project description:The diagnosis of myelodysplastic syndromes (MDS) remains problematic due to the subjective nature of morphological assessment. The reported high frequency of somatic mutations and increased structural variants by array-based cytogenetics have provided potential objective markers of disease however this has been complicated by reports of similar abnormalities in the healthy population. We aimed to identify distinguishing features between those with early MDS and reported healthy individuals by characterising 69 patients who, following a non-diagnostic marrow, developed progressive dysplasia or acute myeloid leukaemia (AML). Targeted sequencing and array based cytogenetics identified a driver mutation and/or structural variant in 91% (63/69) of pre-diagnostic samples with the mutational spectrum mirroring that in the MDS population. When compared with the reported healthy population the mutations detected had significantly greater median variant allele fraction (40% vs 9-10%) and occurred more commonly with additional mutations (≥2 mutations 64% vs. 8%). Furthermore mutational analysis identified a high-risk group of patients with shorter time to disease progression and poorer overall survival. The mutational features in our cohort are distinct from those seen in the healthy population and, even in the absence of definitive disease, can predict outcome. Early detection may allow consideration of intervention in poor risk patients. We performed array based cytogenetics using HumanCytoSNP-12 (Illumina) on 69 patients diagnosed with acute myeloid leukaemia or myelodysplastic syndrome who had a previously non-diagnostic sample. SNP array analysis was performed on all diagnostic samples. In those with a documented abnormality, SNP-A was performed on the corresponding pre-diagnostic sample (n=32).
2015-09-17 | E-GEOD-73074 | biostudies-arrayexpress
Project description:Background: Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer. Identification of ccRCC likely to progress, despite an apparent low risk at the time of surgery, represents a key clinical issue. Methods: From a cohort of adult ccRCC patients (n=443), we selected low-risk tumors progressing within a 5-years average follow-up (progressors: P, n=8) and non-progressing (NP) tumors (n=16). Transcriptome sequencing, miRNA sequencing and proteomics were performed on tissues obtained at surgery. Our work suggests that LXR, FXR and macrophage activation pathways could be critically involved in the inhibition of the progression of low-risk ccRCC. Furthermore, a 10-component classifier could support an early identification of apparently low-risk ccRCC patients.
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Project description:The diagnosis of myelodysplastic syndromes (MDS) remains problematic due to the subjective nature of morphological assessment. The reported high frequency of somatic mutations and increased structural variants by array-based cytogenetics have provided potential objective markers of disease however this has been complicated by reports of similar abnormalities in the healthy population. We aimed to identify distinguishing features between those with early MDS and reported healthy individuals by characterising 69 patients who, following a non-diagnostic marrow, developed progressive dysplasia or acute myeloid leukaemia (AML). Targeted sequencing and array based cytogenetics identified a driver mutation and/or structural variant in 91% (63/69) of pre-diagnostic samples with the mutational spectrum mirroring that in the MDS population. When compared with the reported healthy population the mutations detected had significantly greater median variant allele fraction (40% vs 9-10%) and occurred more commonly with additional mutations (≥2 mutations 64% vs. 8%). Furthermore mutational analysis identified a high-risk group of patients with shorter time to disease progression and poorer overall survival. The mutational features in our cohort are distinct from those seen in the healthy population and, even in the absence of definitive disease, can predict outcome. Early detection may allow consideration of intervention in poor risk patients.
2015-09-17 | GSE73074 | GEO
Project description:The use of low dose hypomethylating agents for patients with myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML) has had made a significant impact. In the past, therapies for these diseases were limited and patients who elected to receive treatment were subject to highly toxic, inpatient chemotherapeutics, which were often ineffective. In the era of hypomethylating agents (azacitidine and decitabine), a patient with high grade MDS or AML with multilineage dysplasia can be offered the alternative of outpatient, relatively low-toxicity therapy. Despite the fact that CR (CR) rates to such agents remain relatively low at 15-20%, a much larger percentage of patients will have clinically significant improvements in hemoglobin, platelet, and neutrophil counts while maintaining good outpatient quality of life. As our clinical experience with azanucleotides expands, questions regarding patient selection, optimal dosing strategy, latency to best response and optimal duration of therapy following disease progression remain, but there is no question that for some patients these agents offer, for a time, an almost miraculous clinical benefit. Ongoing clinical trials in combination and in sequence with conventional therapeutics, with other epigenetically active agents, or in conjunction with bone marrow transplantation continue to provide promise for optimization of these agents for patients with myeloid disease. Although the mechanism(s) responsible for the proven efficacy of these agents remain a matter of some controversy, activity is thought to stem from induction of DNA hypomethylation, direct DNA damage, or possibly even immune modulation; there is no question that they have become a permanent part of the armamentarium against myeloid neoplasms.
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Project description:The main non-small-cell lung cancer (NSCLC) histopathological subtypes are lung adenocarcinomas (LUAD) and lung squamous cell carcinomas (LUSC). To identify candidate progression determinants of NSCLC subtypes, we explored the transcriptomic signatures of LUAD versus LUSC. We then investigated the prognostic impact of the identified tumor-associated determinants. This was done utilizing DNA microarray data from 2,437 NSCLC patients. An independent analysis of a case series of 994 NSCLC was conducted by next-generation sequencing, together with gene expression profiling from GEO (https://www.ncbi.nlm.nih.gov/geo/). This work led us to identify 69 distinct tumor prognostic determinants, which impact on LUAD or LUSC clinical outcome. These included key drivers of tumor growth and cell cycle, transcription factors and metabolic determinants. Such disease determinants appeared vastly different in LUAD versus LUSC, and often had opposite impact on clinical outcome. These findings indicate that distinct tumor progression pathways are at work in the two NSCLC subtypes. Notably, most prognostic determinants would go inappropriately assessed or even undetected when globally investigating unselected NSCLC. Hence, differential consideration for NSCLC subtypes should be taken into account in current clinical evaluation procedures for lung cancer.
| S-EPMC6238974 | biostudies-literature
Project description:Hypomethylating agents (HMAs) improve survival in patients with higher-risk myelodysplastic syndromes (MDS) but are less well-studied in lower-risk disease. We compared the safety and efficacy of low-dose decitabine vs low-dose azacitidine in this group of patients. Adults with low- or intermediate 1-risk MDS or MDS/myeloproliferative neoplasm (MPN), including chronic myelomonocytic leukemia, according to the International Prognostic Scoring System, were randomly assigned using a Bayesian adaptive design to receive either azacitidine 75 mg/m2 intravenously/subcutaneously daily or decitabine 20 mg/m2 intravenously daily for 3 consecutive days on a 28-day cycle. The primary outcome was overall response rate (ORR). Between November 2012 and February 2016, 113 patients were treated: 40 (35%) with azacitidine and 73 (65%) with decitabine. The median age was 70 years; 81% of patients were intermediate 1-risk patients. The median number of cycles received was 9. The ORRs were 70% and 49% (P = .03) for patients treated with decitabine and azacitidine, respectively. Thirty-two percent of patients treated with decitabine became transfusion independent compared with 16% of patients treated with azacitidine (P = .2). Cytogenetic response rates were 61% and 25% (P = .02), respectively. With a median follow-up of 20 months, the overall median event-free survival was 18 months: 20 and 13 months for patients treated with decitabine and azacitidine, respectively (P = .1). Treatment was well tolerated, with a 6-week mortality rate of 0%. The use of low-dose HMAs is safe and effective in patients with lower-risk MDS and MDS/MPN. Their effect on the natural history of lower-risk disease needs to be further studied. This trial was registered at clinicaltrials.gov (identifier NCT01720225).
| S-EPMC5620419 | biostudies-literature
Project description:BackgroundStochastic epigenetic mutations (SEM) reflect a deviation from normal site-specific methylation patterns. Epigenetic mutation load (EML) captures the accumulation of SEMs across an individual's genome and may reflect dysfunction of the epigenetic maintenance system in response to epigenetic challenges.ObjectiveWe investigate whether EML is associated with PD risk and time to events (i.e., death and motor symptom decline).MethodsWe employed logistic regression and Cox proportional hazards regression to assess the association between EML and several outcomes. Our analyses are based on 568 PD patients and 238 controls from the Parkinson's disease, Environment and Genes (PEG) study, for whom blood-based methylation data was available.ResultsWe found an association for PD onset and EML in all genes (OR = 1.90; 95%CI 1.52-2.37) and PD-related genes (OR = 1.87; 95%CI 1.50-2.32). EML was also associated with time to a minimum score of 35 points on the motor UPDRS exam (OR = 1.28; 95%CI 1.06-1.56) and time to death (OR = 1.29, 95%CI 1.11-1.49). An analysis of PD related genes only revealed five intragenic hotspots of high SEM density associated with PD risk.ConclusionOur findings suggest an enrichment of methylation dysregulation in PD patients in general and specifically in five PD related genes. EML may also be associated with time to death and motor symptom progression in PD patients.
| S-EPMC9076404 | biostudies-literature