A5052323199- Cancer Genomics and Diagnostics
- Acute Myeloid Leukemia Research
- Single-cell and spatial transcriptomics
- Hematological disorders and diagnostics
- Epigenetics and DNA Methylation
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Cancer Cells and Metastasis
- Genomics and Phylogenetic Studies
- Sarcoma Diagnosis and Treatment
- CRISPR and Genetic Engineering
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- Hemoglobinopathies and Related Disorders
- DNA Repair Mechanisms
- Genomics and Rare Diseases
- Genomic variations and chromosomal abnormalities
- Pluripotent Stem Cells Research
- Prenatal Screening and Diagnostics
- Evolution and Genetic Dynamics
- Cancer-related Molecular Pathways
- Acute Lymphoblastic Leukemia research
- CAR-T cell therapy research
- Cytomegalovirus and herpesvirus research
- Viral-associated cancers and disorders
- Transplantation: Methods and Outcomes
Oncode Institute
2020-2024
Princess Máxima Center
2019-2024
Genmab (Netherlands)
2023
Radboud University Nijmegen
2019-2023
Radboud Institute for Molecular Life Sciences
2019-2023
Radboud University Medical Center
2019-2023
The collective of somatic mutations in a genome represents record mutational processes that have been operative cell. These can be investigated by extracting relevant patterns from sequencing data.
Genetic instability is a major concern for successful application of stem cells in regenerative medicine. However, the mutational consequences most applied cell therapy humans, hematopoietic transplantation (HSCT), remain unknown. Here we characterized mutation burden and progenitor (HSPCs) human HSCT recipients their donors using whole-genome sequencing. We demonstrate that majority transplanted HSPCs did not display altered accumulation. some recipients, identified multiple with an...
Children show a higher incidence of leukemia compared to young adolescents, yet their cells have less age-related (oncogenic) somatic mutations. Newborns with Down syndrome an even risk developing leukemia, which is thought be driven by mutations that accumulate during fetal development. To characterize mutation accumulation in individual stem and progenitor karyotypically normal fetuses, we clonally expanded single performed whole-genome sequencing. We found rate haematopoietic development...
Abstract Acquisition of oncogenic mutations with age is believed to be rate limiting for carcinogenesis. However, the incidence leukemia in children higher than young adults. Here we compare somatic across pediatric acute myeloid (pAML) patient-matched leukemic blasts and hematopoietic stem progenitor cells (HSPC), as well HSPCs from age-matched healthy donors. bone marrow have limited genetic relatedness share few cell origin malignant blasts, suggesting polyclonal hematopoiesis patients...
By replicating damaged nucleotides, error-prone DNA translesion synthesis (TLS) enables the completion of replication, albeit at expense fidelity. TLS helix-distorting lesions, that usually have reduced capacity basepairing, comprises insertion opposite lesion followed by extension, latter in particular polymerase ζ (Pol ζ). However, little is known about involvement Pol non- or poorly-distorting, but miscoding, lesions such as O
Detection of somatic mutations in single cells has been severely hampered by technical limitations whole-genome amplification. Novel technologies including primary template-directed amplification (PTA) significantly improved the accuracy single-cell sequencing (WGS) but still generate hundreds artifacts per reaction. We developed a comprehensive bioinformatic workflow, called PTA Analysis Toolbox (PTATO), to accurately detect base substitutions, insertions-deletions (indels), and structural...
Abstract Detection of somatic mutations in single cells has been severely hampered by technical limitations whole genome amplification. Novel technologies including primary template-directed amplification (PTA) significantly improved the accuracy single-cell sequencing (WGS), but still generate hundreds artefacts per reaction. We developed a comprehensive bioinformatic workflow, called PTA Analysis Toolkit (PTATO), to accurately detect base substitutions, small insertions and deletions...
Abstract Children show a higher incidence of leukaemia compared with young adolescents, yet their cells are less damaged because age. Down syndrome (DS) have an even risk developing during the first years life. The presence constitutive trisomy chromosome 21 (T21) in DS acts as genetic driver for development, however, additional oncogenic mutations required. Therefore, T21 provides opportunity to better understand leukaemogenesis children. Here, we describe increased childhood from somatic...
Abstract Background The collective of somatic mutations in a genome represents record mutational processes that have been operative cell. These can be investigated by extracting relevant patterns from sequencing data. Results Here, we present the next version MutationalPatterns, an R/Bioconductor package, which allows in-depth analysis catalogues single and double base substitutions as well small insertions deletions. Major features package include possibility to perform regional mutation...
Hematopoietic stem and progenitor cells (HSPCs) gradually accumulate DNA mutations during a lifespan, which can contribute to age-associated diseases such as leukemia. Characterizing mutation accumulation improve understanding of the etiology diseases. Presented here is method catalogue somatic in individual HSPCs, based on whole-genome sequencing (WGS) clonal primary cell cultures. Mutations that are present original shared by all culture, whereas acquired vitro after sorting subset cells....
Abstract Background We previously reported a familial thyroid follicular cell carcinoma (FCC) in large number of Dutch German longhaired pointers and identified two deleterious germline mutations the TPO gene associated with disease predisposition. However, somatic mutation profile FCC dogs has not been investigated at genome-wide scale. Results Herein, we comprehensively that potentially contribute to inherited tumor formation progression using high depth whole-genome sequencing. A GNAS...
FKBP5 is a 115-kb-long glucocorticoid-inducible gene implicated in psychiatric disorders. To investigate the complexities of chromatin interaction frequencies at topologically associated domain (TAD), we deployed 15 one-to-all capture viewpoints near promoters, enhancers, introns, and CTCF-loop anchors. This revealed "one-TAD-one-gene" structure encompassing promoter its enhancers. The two glucocorticoid-stimulated enhancers roam entire TAD while displaying subtle cell type-specific...
Mitochondria are small organelles that play an essential role in the energy production of eukaryotic cells. Defects their genomes associated with diseases, such as aging and cancer. Here, we analyzed mitochondrial 532 whole-genome sequencing samples from cancers normal clonally expanded single We show mitochondria cells accumulate mutations age most found cancer result healthy mutation accumulation. also HSPCs patients leukemia have increased load. Finally, secondary pediatric chemotherapy...
Summary Rhabdomyosarcomas (RMS) are mesenchyme-derived tumors and the most common childhood soft tissue sarcomas. Treatment is intense, with a nevertheless poor prognosis for high-risk patients. Discovery of new therapies would benefit from additional preclinical models. Here we describe generation collection pediatric RMS tumor organoid (tumoroid) models comprising all major subtypes. For aggressive tumors, tumoroid can often be established within four to eight weeks, indicating feasibility...
Abstract Topologically associated domains (TADs) are defined as regions of self-interaction. To date, it is unclear how to reconcile TAD structure with CTCF site orientation, which known coordinate chromatin loops anchored by Cohesin rings at convergent pairs. We first approached this problem 4C analysis the FKBP5 locus. This uncovered a loop encompassing but not its entire TAD. However, adjacent sites were able form ‘back-up’ and these located boundaries. then analysed spatial distribution...
Hematopoietic stem and progenitor cells (HSPCs) gradually accumulate DNA mutations during a lifespan, which can contribute to age-associated diseases such as leukemia. Characterizing mutation accumulation improve understanding of the etiology diseases. Presented here is method catalogue somatic in individual HSPCs, based on whole-genome sequencing (WGS) clonal primary cell cultures. Mutations that are present original shared by all culture, whereas acquired vitro after sorting subset cells....
<div>Abstract<p>Acquisition of oncogenic mutations with age is believed to be rate limiting for carcinogenesis. However, the incidence leukemia in children higher than young adults. Here we compare somatic across pediatric acute myeloid (pAML) patient-matched leukemic blasts and hematopoietic stem progenitor cells (HSPC), as well HSPCs from age-matched healthy donors. bone marrow have limited genetic relatedness share few cell origin malignant blasts, suggesting polyclonal...
<div>Abstract<p>Acquisition of oncogenic mutations with age is believed to be rate limiting for carcinogenesis. However, the incidence leukemia in children higher than young adults. Here we compare somatic across pediatric acute myeloid (pAML) patient-matched leukemic blasts and hematopoietic stem progenitor cells (HSPC), as well HSPCs from age-matched healthy donors. bone marrow have limited genetic relatedness share few cell origin malignant blasts, suggesting polyclonal...
<p>Supplementary Table S1-10 providing details on study cohorts and sequencing results</p>
<p>Supplementary Figures S1-S6 with figure legends</p>