Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mutational Mechanisms in Multiply Relapsed Pediatric Acute Lymphoblastic Leukemia

ABSTRACT: Pediatric acute lymphoblastic leukemia (ALL) is marked by low mutational load at initial diagnosis, which increases at relapse. To determine which processes are active in (relapsed) ALL and how they behave during disease progression before and after therapy, we performed whole genome sequencing on tumor samples of 29 multiply relapsed ALL patients. Mutational load increased upon relapse in 28 patients and every subsequent relapse in 22 patients, with UV-like damage, APOBEC activity, reactive oxygen species, thiopurine-associated damage and an unknown therapy component driving mutagenesis. Thiopurines were the most prominent source of new mutations in relapse, affecting over half of the studied patients and causing potential relapse-driving mutations in multiple patients. Mutational processes often affected patients over longer time periods, but could also occur in isolated events, suggesting the requirement of additional triggers. Our data pose mutational processes as prominent secondary drivers with an important role in ALL development and progression.

PROVIDER: EGAS00001007900 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Json Xml

Similar Datasets

PMCDS000ABS - samples

Project description:Pediatric acute lymphoblastic leukemia (ALL) is marked by low mutational load at initial diagnosis, which increases at relapse. The elevated mutational load at relapse can partly be explained by at least two therapy-related effects and a combination of therapy and underlying mismatch repair deficiency. However, our understanding of the type and timing of mutational mechanisms in relapsed ALL is limited, and it is unclear to what extent mutational processes contribute to disease progression. We collected a cohort of 29 Dutch ALL patients across multiple treatment protocols who had multiple relapses. Using whole genome sequencing of the sequential tumor samples of each patient we were able to distinguish the mutational processes active in relapsed ALL and could track the activity of mutational processes over time. This allowed us to investigate whether subtype-specific mutational processes at diagnosis can continue in relapse or emerge at relapse if absent in initial diagnosis. Furthermore, we assessed whether the activity of mutational processes contributed to disease development and relapse.

| EGAD00001015401 | EGA

Gene expression profiles associated with pediatric relapsed AML

Project description:In high income countries 90% of the patients achieve complete remission after induction chemotherapy. However, 30-40% of these patients suffer from relapse. These patients face a dismal prognosis, as the majority (>60%) of relapsed patients die within 5 years. As a result, outcome for pediatric acute myeloid leukemia (AML) patients remains poor and has stabilized over the past 15 years. To prevent or better treat relapse of AML is the best option to improve outcome. Despite patient specific differences, most patients do respond to initial therapy. This suggests that at relapse, mechanisms are active that cause the altered response to chemotherapy. Detailed understanding of mechanisms that cause relapse remain largely elusive. To gain insight in the molecular pathways that characterize relapsed AML, we performed genome wide gene expression profiling on paired initial diagnosis and relapsed AML samples of 23 pediatric AML patients. We used pathway analysis to find which molecular pathways are involved in altered gene expression between diagnosis and relapse samples of individual AML patients. 23 paired diagnosis and relapse bone marrow or peripheral blood samples were collected and cryo-preserved. They were later thawed and processed for hybridization to Affymetrix U133 Plus 2.0 arrays.

2015-05-07 | E-GEOD-52891 | biostudies-arrayexpress

Gene expression profiles associated with pediatric relapsed AML

2015-05-07 | GSE52891 | GEO

Whole exome sequencing analyses of human, IDH2-mutated, acute myeloid leukemia samples from patients before or during treatment with Enasidenib.

Project description:Mutations in isocitrate dehydrogenase 2 (IDH2) occur in many cancers including Acute Myeloid Leukemia (AML). In preclinical models mutant IDH2 causes partial hemopoietic differentiation arrest. Recently, we showed that single agent Enasidenib, a first-in-class, selective mutant IDH2 inhibitor, produces a 40% response in relapsed/refractory AML patients by promoting differentiation. Yet, the rate, extend and duration of the clinical benefits of Enasidenib vary from one patient to another. To investigate how the genetic mutational landscape, at baseline or at relapse, contributes in modulating response to Enasidenib, WES analyses on FACS-sorted blasts from baseline, best response and/or relapse samples from 16 Enasidenib-treated patients were performed. WES analyses were also performed on the CD3+ cells from the same patients, which may be used as germinal control samples.

2018-08-13 | E-MTAB-6299 | biostudies-arrayexpress

PMCDS000ABN - samples

Project description:Molecular characterization of 41 tumors from 17 individuals with CMMRD to gain a better understandig of mutational processes driving subsequent tumor development. The molecular characterization includes the investigation of tumor mutational load and mutational signatures.

| EGAD00001015157 | EGA

PMCDS000ABO - samples

| EGAD00001015158 | EGA

Analysis of non-relapsed and relapsed adult type granulosa cell tumors suggests stable transcriptomes during tumor progression

Project description:Adult-type granulosa cell tumor (AGCT) is a rare ovarian malignancy characterized by slow growth and hormonal activity. The prognosis of AGCT is generally favorable, but one-third of patients with low-stage disease experience a late relapse, and over half of them die of AGCT. To identify markers that would distinguish patients at risk for relapse, we performed Lexogen QuantSeq 3’ mRNA sequencing on formalin-fixed paraffin-embedded, archival AGCT tissue samples tested positive for the pathognomonic FOXL2-mutation. We compared the transcriptomic profiles of 14 non-relapsed archival primary AGCTs (follow-up time 17-26 years after diagnosis) with 13 relapsed primary AGCTs (follow-up time 1.7-18 years) and eight relapsed tumors (follow-up time 2.8-18.9 years). Non-relapsed and relapsed primary AGCTs had similar transcriptomic profiles. In relapsed tumors three genes were differentially expressed: plasmalemma vesicle associated protein (PLVAP) was upregulated (p=0.01), whereas argininosuccinate synthase 1 (ASS1) (p=0.01) and perilipin 4 (PLIN4) (p=0.02) were downregulated. PLVAP upregulation was validated using tissue microarray RNA in situ hybridization. In our patient cohort with extremely long follow-up, we observed similar gene expression patterns in both primary AGCT groups suggesting that relapse is not driven by transcriptomic changes. These results reinforce earlier findings that molecular markers do not predict AGCT behavior or risk of relapse.

2022-03-23 | GSE190942 | GEO

Epigenomic Evolution of Diffuse Large B-cell Relapse

Project description:Here we characterize an association between disease progression and DNA methylation in Diffuse Large B cell Lymphoma (DLBCL). By profiling genome-wide DNA methylation at single base-pair resolution in thirteen DLBCL diagnosis-relapse sample pairs, we show DLBCL patients exhibit heterogeneous evolution of tumor methylomes during relapse. We identify differentially methylated regulatory elements and determine a relapse–associated methylation signature converging on key pathways such as transforming growth factor beta (TGF-beta) receptor activity. We also observe decreased intra-tumor methylation heterogeneity from diagnosis to relapsed tumor samples. Relapse-free patients display lower intra-tumor methylation heterogeneity at diagnosis compared to relapsed patients in an independent validation cohort. Furthermore, intra-tumor methylation heterogeneity is predictive of time to relapse. Therefore, we propose that epigenomic heterogeneity may support or drive the relapse phenotype and can be used to predict DLBCL relapse. Using ERRBS, we profiled genome-wide DNA methylation patterns of non-relapse DLBCL tumor samples at diagnosis, relaspe DLBCL patient samples at diagnosis and relaspe.

2015-04-14 | E-GEOD-66329 | biostudies-arrayexpress

Expression data from transplanted HCmel3 mouse melanomas relapsing to adoptive T-cell therapy in vivo

Project description:Adoptive cell therapies (ACT) with cytotoxic T-cell targeting melanocytic antigens can achieve remissions in metastatic melanoma patients, but tumours frequently relapse. To study the underlying mechanisms of resistance we have generated a genetically engineered mouse melanoma model that faithfully recapitulates tumour regression, remission and relapse as seen in patients. HCmel3 mouse melanoma cells were injected into syngneic C57/BL6 (H-2b) mice. We performed transcriptional profiling of control, relapsed and re-transplanted relapsed tumours to characterize the changes in gene expression patterns associated with the respective treament conditions. In addition, we analysed the transcription profile of ACT relapsed melanoma cultures in vitro and the transcriptional response to the inflammatory cytokine Tnf-alpha. The study aimed to identify molecular mechanisms contributing to ACT resistance to optimize therapeutic regimens in the clinic. Total RNA obtained from five biological replicates (rep) of control, relapsed and re-transplanted HCmel3 mouse melanomas in vivo and two biological replicates (rep) of HCmel3 cells, HCmel3-R (relapse) cells and Tnf-alpha treated HCmel3 cells in vitro.

2012-10-10 | E-GEOD-40213 | biostudies-arrayexpress

Gene expression profiling of primary HER2-positive breast cancers treated with adjuvant trastuzumab

Project description:Trastuzumab, a humanized monoclonal antibody directed to the HER2 protein, is the standard-of-care treatment for patients with HER2 positive breast cancer, reducing the risk of relapse and death in patients. Nonetheless, some patients relapse after treatment, underscoring the need to identify patients for whom chemotherapy + trastuzumab is adequate versus patients requiring additional drugs. To search for genes predictive of relapse in HER2-positive breast carcinoma patients treated with adjuvant trastuzumab, we conducted gene expression profiling analysis in 53 cases treated in the clinic with doxorubicin/paclitaxel (AT) followed by cyclophosphamide/methotrexate/fluorouracil (CMF) and trastuzumab. Gene expression profiling was performed using RNA from formalin-fixed paraffin-embedded tissues from 53 patients with primary HER2-positive (HER2+) tumors. The series consists in 23 relapsed and 30 non-relapsed cases with similar clinical-pathological characteristics (size, pathological lymph node involvement and estrogen receptor positivity) (3-year median follow up).

2015-10-19 | E-GEOD-55348 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data