A5022409006- Renal and related cancers
- Cancer Genomics and Diagnostics
- Mathematical Biology Tumor Growth
- Neuroblastoma Research and Treatments
- Pancreatic and Hepatic Oncology Research
- Microtubule and mitosis dynamics
- Genomics and Phylogenetic Studies
- Prenatal Screening and Diagnostics
- Reproductive Biology and Fertility
- Evolution and Genetic Dynamics
- Renal cell carcinoma treatment
- Cancer Cells and Metastasis
- Lung Cancer Research Studies
- Genomics and Rare Diseases
- Epigenetics and DNA Methylation
- Sarcoma Diagnosis and Treatment
- Genomic variations and chromosomal abnormalities
- Glioma Diagnosis and Treatment
- Long-Term Effects of COVID-19
- PARP inhibition in cancer therapy
- Genetic Syndromes and Imprinting
- Immune cells in cancer
- Protein Degradation and Inhibitors
- Chromatin Remodeling and Cancer
- Intestinal Malrotation and Obstruction Disorders
Lund University
2015-2024
Skåne University Hospital
2019-2024
Karolinska Institutet
2023
Understanding the complete immune cell composition of human neuroblastoma (NB) is crucial for development immunotherapeutics. Here, we perform single-cell RNA sequencing (scRNA-seq) on 19 NB samples coupled with multiplex immunohistochemistry, survival analysis, and comparison normal fetal adrenal gland data. We provide a comprehensive landscape characterize cell-state changes from tissue to NB. Our analysis reveals 27 subtypes, including distinct subpopulations myeloid, NK, B, T cells....
Genetic differences among neoplastic cells within the same tumour have been proposed to drive cancer progression and treatment failure. Whether data on intratumoral diversity can be used predict clinical outcome remains unclear. We here address this issue by quantifying genetic in a set of chemotherapy-treated childhood tumours. By analysis multiple samples from seven patients we demonstrate all analysed after chemotherapy, typically presenting as clones single millimetre-sized sample...
Clear cell sarcoma of the kidney (CCSK) is second most common pediatric renal tumor. Two recurrent genetic aberrations have been described in CCSK. One a fusion YWHAE and NUTM2B/E , other an internal tandem duplication (ITD) BCOR gene. Here it shown that – ITD are mutually exclusive events activated different downstream signaling systems. This has important diagnostic implications opens up for further mechanistic studies CCSK pathogenesis. © 2015 Wiley Periodicals, Inc.
Abstract Darwinian evolution of tumor cells remains underexplored in childhood cancer. We here reconstruct the evolutionary histories 56 pediatric primary tumors, including 24 neuroblastomas, Wilms and 8 rhabdomyosarcomas. Whole-genome copy-number whole-exome mutational profiling multiple regions per were performed, followed by clonal deconvolution to a phylogenetic tree for each tumor. Overall, 88% tumors exhibited genetic variation among regions. This variability typically emerged through...
Significance Aneuploidy, denoting cells with an abnormal number of chromosomes, is a common phenomenon in cancer. Another finding cancer chromosomal instability, condition which change their content at high rate. It clear that instability can lead to aneuploidy, but whether the opposite true has been much debated field biology. The concept aneuploidy automatically triggers propagated scientific literature recent years. Here, we show does not, on its own, even when acquire chromosome...
The global methylation profile and the mutational status of 633 specific epigenetic regulators were analyzed in pediatric tumor clear cell sarcoma kidney (CCSK). Methylation array analyses 30 CCSKs revealed CCSK DNA to be globally hypermethylated compared Wilms tumor, normal fetal kidney, adult kidney. aberrant pattern was associated with activation genes involved embryonic processes silencing linked function. No regulator recurrently mutated our cohort, but a mutation key EZH2 discovered...
Despite aggressive treatment, the 5-year event-free survival rate for children with high-risk neuroblastoma is <50%. While most patients initially respond to often complete clinical remission, many eventually relapse therapy-resistant tumors. Novel therapeutic alternatives that prevent recurrence of tumors are urgently needed. To understand adaptation under therapy, we analyzed transcriptomic landscape in 46 tumor samples collected before (PRE) or after (POST) treatment from 22 patients. RNA...
Neuroblastoma (NB) is one of the most lethal childhood cancers due to its propensity become treatment resistant. By spatial mapping subclone geographies before and after chemotherapy across 89 tumor regions from 12 NBs, we find that densely packed territories closely related subclones present at diagnosis are replaced under effective by islands distantly survivor subclones, originating a different recent ancestor compared lineages dominating treatment. Conversely, in tumors progressed...
An unbalanced chromosome number (aneuploidy) is present in most malignant tumours and has been attributed to mitotic mis-segregation of chromosomes. However, recent studies have shown a relatively high rate chromosomal also non-neoplastic human cells, while the frequency aneuploid cells remains low throughout life normal tissues. This implies that newly formed are subject negative selection healthy tissues attenuation this could contribute aneuploidy cancer. To test this, we modelled...
Phylogenetic reconstruction of cancer cell populations remains challenging. There is a particular lack tools that deconvolve clones based on copy number aberration analyses multiple tumor biopsies separated in time and space from the same patient. This has hampered investigations tumors rich aneuploidy but few point mutations, as many childhood cancers high-risk adult cancer. Here, we present DEVOLUTION, an algorithm for subclonal deconvolution followed by phylogenetic bulk genotyping data....
Abstract Purpose: While patients with intermediate-risk (IR) Wilms tumors now have an overall survival (OS) rate of almost 90%, those affected by high-stage diffuse anaplasia OS only around 50%. We here identify key events in the pathogenesis mapping cancer cell evolution over anatomic space tumors. Experimental Design: spatially mapped subclonal landscapes a retrospective cohort 20 using high-resolution copy-number profiling and TP53 mutation analysis followed clonal deconvolution...
Abstract Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease. The only option for curative treatment is resection of the tumor followed by standard adjuvant chemotherapy. Yet, early relapse due to chemoresistance almost inevitable. Herein, we delineated genetic intratumor heterogeneity in resected PDAC, with aim identify evolutionary patterns that may be associated overall survival (OS) following intent. Potential relationships adjacent immune microenvironment were also...
Therapeutic activation of tumor-infiltrating lymphocytes using monoclonal antibodies targeting PD1 or PD-L1 (immune checkpoint inhibitors-ICIs) has revolutionized treatment specific solid tumors in adult cancer patients, and much hope been placed on a similar effect relapsed refractory pediatric tumors. Recent clinical trials have disappointingly shown an almost nonexistent response rate, while case reports demonstrated that some patients do achieve durable responses when treated with this type drug.
Abstract Wilms tumors in patients with constitutional WT1 mutations are examples of Knudson's tumor suppressor paradigm, somatic inactivation the second allele occurring through 11p loss heterozygosity. The time point this hit has remained unknown. We analyzed seven from two by whole exome sequencing and genomic array. All exhibited wild type uniparental isodisomy. Each had a unique breakpoint 11p, typically accompanied private activating mutation CTNNB1 . Hence, convergent evolution rather...
Whether chromosome abnormalities observed in tumor cells may some cases reflect low‐grade somatic mosaicism for anomalies present already at zygote formation, rather than acquired mutations, has long remained a speculation. We here report patient with Wilms tumor, where constitutional of trisomy 8 was detected previously healthy 2 ½‐year‐old boy. Single Nucleotide Polymorphism (SNP) array analysis tissue revealed complex distribution allele frequencies that could not be explained solely by...
Abstract Somatic mosaicism, the presence of genetically distinct cells within an organism, has been increasingly associated with human morbidity, ranging from being a cause rare syndromes to risk factor for common disorders such as malignancy and cardiovascular disease. Previous studies interrogating normal prevalence somatic mosaicism have focused on adults. We here present estimate baseline frequency mosaic copy number variation (CNV) at time around birth, by sampling eight different...
The survival rate for childhood acute lymphoblastic leukaemia (ALL) has improved over time, due to uniform treatment with risk-adapted therapy developed through international collaboration. ALLTogether protocol (EUDRACT 2018–001795-38; ClinicalTrials.gov: NCT03911128) replaced the NOPHO ALL2008 (ALL2008; EUDRACT in Sweden 2019. introduced a high dose of intravenous asparaginase during early induction combined dexamethasone. Both and glucocorticoids lead transient coagulopathy. Asparagine...
<p>Supplementary Table 3. Table. Sample list with TP53 status. All 20 WT cases and their corresponding samples are listed. ‘Sample position’ refers to the individual sample its position in a certain paraffin block (see Figure 1 for details.) IR= intermediate risk, BT= blastemal type, DA= diffuse anaplasia. Headings marked grey show sequencing results; wt=wild mut=mutation, NA= not annotated (i.e. sequenced), aa= amino acid, REF= reference nucleotide, ALT= alternative ref= number of...
<p>Supplementary Table 4. Segmental aberrations. All 20 Wilms tumor (WT) cases and their corresponding samples are listed. ‘Sample position’ refers to the individual sample its position in a certain paraffin block (see Figure 1 for details.) For each genetic event following information is given: ploidy level (Ploidy), chromosome (chr), genomic start end positions, events annotated as gain, loss, CNNI (copy neutral imbalance) or homozygous length of aberration (bp), which chromosomal...