| 1. |
- Van den Eynden, Jimmy, 1977, et al.
(author)
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The genetic structure of the Belgian population
- 2018
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In: Human Genomics. - : Springer Science and Business Media LLC. - 1473-9542 .- 1479-7364. ; 12:6
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Journal article (peer-reviewed)abstract
- Background: National and international efforts like the 1000 Genomes Project are leading to increasing insights in the genetic structure of populations worldwide. Variation between different populations necessitates access to population-based genetic reference datasets. These data, which are important not only in clinical settings but also to potentiate future transitions towards a more personalized public health approach, are currently not available for the Belgian population. Results: To obtain a representative genetic dataset of the Belgian population, participants in the 2013 National Health Interview Survey (NHIS) were invited to donate saliva samples for DNA analysis. DNA was isolated and single nucleotide polymorphisms (SNPs) were determined using a genome-wide SNP array of around 300,000 sites, resulting in a high-quality dataset of 189 samples that was used for further analysis. A principal component analysis demonstrated the typical European genetic constitution of the Belgian population, as compared to other continents. Within Europe, the Belgian population could be clearly distinguished from other European populations. Furthermore, obvious signs from recent migration were found, mainly from Southern Europe and Africa, corresponding with migration trends from the past decades. Within Belgium, a small north-west to south-east gradient in genetic variability was noted, with differences between Flanders and Wallonia. Conclusions: This is the first study on the genetic structure of the Belgian population and its regional variation. The Belgian genetic structure mirrors its geographic location in Europe with regional differences and clear signs of recent migration.
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| 2. |
- Van, T. L., et al.
(author)
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Simultaneous discovery of cancer subtypes and subtype features by molecular data integration
- 2016
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In: Bioinformatics. - Oxford : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 32:17, s. 445-454
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Journal article (peer-reviewed)abstract
- Motivation: Subtyping cancer is key to an improved and more personalized prognosis/treatment. The increasing availability of tumor related molecular data provides the opportunity to identify molecular subtypes in a data-driven way. Molecular subtypes are defined as groups of samples that have a similar molecular mechanism at the origin of the carcinogenesis. The molecular mechanisms are reflected by subtype-specific mutational and expression features. Data-driven subtyping is a complex problem as subtyping and identifying the molecular mechanisms that drive carcinogenesis are confounded problems. Many current integrative subtyping methods use global mutational and/or expression tumor profiles to group tumor samples in subtypes but do not explicitly extract the subtype-specific features. We therefore present a method that solves both tasks of subtyping and identification of subtype-specific features simultaneously. Hereto our method integrates' mutational and expression data while taking into account the clonal properties of carcinogenesis. Key to our method is a formalization of the problem as a rank matrix factorization of ranked data that approaches the subtyping problem as multi-view bi-clustering. Results: We introduce a novel integrative framework to identify subtypes by combining mutational and expression features. The incomparable measurement data is integrated by transformation into ranked data and subtypes are defined as multi-view bi-clusters. We formalize the model using rank matrix factorization, resulting in the SRF algorithm. Experiments on simulated data and the TCGA breast cancer data demonstrate that SRF is able to capture subtle differences that existing methods may miss.
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| 3. |
- Ashouri, Arghavan, 1987, et al.
(author)
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Pan-cancer transcriptomic analysis associates long non-coding RNAs with key mutational driver events
- 2016
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Journal article (peer-reviewed)abstract
- Thousands of long non-coding RNAs (lncRNAs) lie interspersed with coding genes across the genome, and a small subset has been implicated as downstream effectors in oncogenic pathways. Here we make use of transcriptome and exome sequencing data from thousands of tumours across 19 cancer types, to identify lncRNAs that are induced or repressed in relation to somatic mutations in key oncogenic driver genes. Our screen confirms known coding and non-coding effectors and also associates many new lncRNAs to relevant pathways. The associations are often highly reproducible across cancer types, and while many lncRNAs are co-expressed with their protein-coding hosts or neighbours, some are intergenic and independent. We highlight lncRNAs with possible functions downstream of the tumour suppressor TP53 and the master antioxidant transcription factor NFE2L2. Our study provides a comprehensive overview of lncRNA transcriptional alterations in relation to key driver mutational events in human cancers.
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| 4. |
- Bandaru, Sashidar, et al.
(author)
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Targeting filamin A reduces macrophage activity and atherosclerosis. : Filamin A in atherogenesis
- 2019
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In: Circulation. - 1524-4539. ; 140:1, s. 67-79
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Journal article (peer-reviewed)abstract
- The actin-binding protein FLNA (filamin A) regulates signal transduction important for cell locomotion, but the role of macrophage-specific FLNA during atherogenesis has not been explored.We analyzed FLNA expression in human carotid atherosclerotic plaques by immunofluorescence. We also produced mice with Flna-deficient macrophages by breeding conditional Flna-knockout mice ( Flna o/fl) with mice expressing Cre from the macrophage-specific lysosome M promoter ( LC). Atherosclerosis in vivo was studied by transplanting bone marrow from male Flna o/fl/ LC mice to atherogenic low-density lipoprotein receptor-deficient ( Ldlr-/-) mice; and by infecting Flna o/fl and Flna o/fl/ LC mice with AdPCSK9 (adenoviral vector overexpressing proprotein convertase subtilisin/kexin type 9). Furthermore, C57BL/6 mice were infected with AdPCSK9 and then treated with the calpain inhibitor calpeptin to inhibit FLNA cleavage.We found that macrophage FLNA expression was higher in advanced than in intermediate human atherosclerotic plaques. Flna o/fl/ LC macrophages proliferated and migrated less than controls; expressed lower levels of phosphorylated AKT and ERK1/2; exhibited reduced foam cell formation and lipid uptake; and excreted more lipids. The deficiency of Flna in macrophages markedly reduced the size of aortic atherosclerotic plaques in both Ldlr-/-BMT: Flnao/fl/LC and AdPCSK9-infected Flna o/fl/ LC mice. Intima/media ratios and numbers of CD68-positive macrophages in atherosclerotic plaques were lower in Flna-deficient mice than in control mice. Moreover, we found that STAT3 interacts with a calpain-cleaved carboxyl-terminal fragment of FLNA. Inhibiting calpain-mediated FLNA cleavage with calpeptin in macrophages reduced nuclear levels of phosphorylated STAT3, interleukin 6 secretion, foam cell formation, and lipid uptake. Finally, calpeptin treatment reduced the size of atherosclerotic plaques in C57BL/6 mice infected with AdPCSK9.Genetic inactivation of Flna and chemical inhibition of calpain-dependent cleavage of FLNA impaired macrophage signaling and function, and reduced atherosclerosis in mice, suggesting that drugs targeting FLNA may be useful in the treatment of atherosclerosis.
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| 5. |
- Borenäs, Marcus, et al.
(author)
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ALK ligand ALKAL2 potentiates MYCN-driven neuroblastoma in the absence of ALK mutation
- 2021
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In: EMBO Journal. - : John Wiley & Sons. - 0261-4189 .- 1460-2075. ; 40:3
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Journal article (peer-reviewed)abstract
- High‐risk neuroblastoma (NB) is responsible for a disproportionate number of childhood deaths due to cancer. One indicator of high‐risk NB is amplification of the neural MYC (MYCN) oncogene, which is currently therapeutically intractable. Identification of anaplastic lymphoma kinase (ALK) as an NB oncogene raised the possibility of using ALK tyrosine kinase inhibitors (TKIs) in treatment of patients with activating ALK mutations. 8–10% of primary NB patients are ALK‐positive, a figure that increases in the relapsed population. ALK is activated by the ALKAL2 ligand located on chromosome 2p, along with ALK and MYCN, in the “2p‐gain” region associated with NB. Dysregulation of ALK ligand in NB has not been addressed, although one of the first oncogenes described was v‐sis that shares > 90% homology with PDGF. Therefore, we tested whether ALKAL2 ligand could potentiate NB progression in the absence of ALK mutation. We show that ALKAL2 overexpression in mice drives ALK TKI‐sensitive NB in the absence of ALK mutation, suggesting that additional NB patients, such as those exhibiting 2p‐gain, may benefit from ALK TKI‐based therapeutic intervention.
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| 6. |
- Borenäs, Marcus, et al.
(author)
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ALK signaling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition
- 2024
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In: Proceedings of the National Academy of Sciences of the United States of America. - 1091-6490. ; 121:1
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Journal article (peer-reviewed)abstract
- High-risk neuroblastoma (NB) is a significant clinical challenge. MYCN and Anaplastic Lymphoma Kinase (ALK), which are often involved in high-risk NB, lead to increased replication stress in cancer cells, suggesting therapeutic strategies. We previously identified an ATR (ataxia telangiectasia and Rad3-related)/ALK inhibitor (ATRi/ALKi) combination as such a strategy in two independent genetically modified mouse NB models. Here, we identify an underlying molecular mechanism, in which ALK signaling leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. The importance of ALK inhibition is supported by mouse data, in which ATRi monotreatment resulted in a robust initial response, but subsequent relapse, in contrast to a 14-d ALKi/ATRi combination treatment that resulted in a robust and sustained response. Finally, we show that the remarkable response to the 14-d combined ATR/ALK inhibition protocol reflects a robust differentiation response, reprogramming tumor cells to a neuronal/Schwann cell lineage identity. Our results identify an ability of ATR inhibition to promote NB differentiation and underscore the importance of further exploring combined ALK/ATR inhibition in NB, particularly in high-risk patient groups with oncogene-induced replication stress.
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| 7. |
- Chuang, Tzu-Po, et al.
(author)
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ALK fusion NSCLC oncogenes promote survival and inhibit NK cell responses via SERPINB4 expression
- 2023
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In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 120:8
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Journal article (peer-reviewed)abstract
- Anaplastic lymphoma kinase (ALK) fusion variants in Non-Small Cell Lung Cancer (NSCLC) consist of numerous dimerizing fusion partners. Retrospective investigations suggest that treatment benefit in response to ALK tyrosine kinase inhibitors (TKIs) differs dependent on the fusion variant present in the patient tumor. Therefore, under -standing the oncogenic signaling networks driven by different ALK fusion variants is important. To do this, we developed controlled inducible cell models expressing either Echinoderm Microtubule Associated Protein Like 4 (EML4)-ALK-V1, EML4-ALK-V3, Kinesin Family Member 5B (KIF5B)-ALK, or TRK-fused gene (TFG)-ALK and investi-gated their transcriptomic and proteomic responses to ALK activity modulation together with patient-derived ALK-positive NSCLC cell lines. This allowed identification of both common and isoform-specific responses downstream of these four ALK fusions. An inflammatory signature that included upregulation of the Serpin B4 serine protease inhibitor was observed in both ALK fusion inducible and patient-derived cells. We show that Signal transducer and activator of transcription 3 (STAT3), Nuclear Factor Kappa B (NF-kappa B) and Activator protein 1 (AP1) are major transcriptional regulators of SERPINB4 downstream of ALK fusions. Upregulation of SERPINB4promotes survival and inhibits natural killer cell-mediated cytotoxicity, which has potential for therapeutic impact targeting the immune response together with ALK TKIs in NSCLC.
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| 8. |
- Elliott, Kerryn, et al.
(author)
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Elevated pyrimidine dimer formation at distinct genomic bases underlies promoter mutation hotspots in UV-exposed cancers.
- 2018
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In: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 14:12
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Journal article (peer-reviewed)abstract
- Sequencing of whole cancer genomes has revealed an abundance of recurrent mutations in gene-regulatory promoter regions, in particular in melanoma where strong mutation hotspots are observed adjacent to ETS-family transcription factor (TF) binding sites. While sometimes interpreted as functional driver events, these mutations are commonly believed to be due to locally inhibited DNA repair. Here, we first show that low-dose UV light induces mutations preferably at a known ETS promoter hotspot in cultured cells even in the absence of global or transcription-coupled nucleotide excision repair (NER). Further, by genome-wide mapping of cyclobutane pyrimidine dimers (CPDs) shortly after UV exposure and thus before DNA repair, we find that ETS-related mutation hotspots exhibit strong increases in CPD formation efficacy in a manner consistent with tumor mutation data at the single-base level. Analysis of a large whole genome cohort illustrates the widespread contribution of this effect to recurrent mutations in melanoma. While inhibited NER underlies a general increase in somatic mutation burden in regulatory elements including ETS sites, our data supports that elevated DNA damage formation at specific genomic bases is at the core of the prominent promoter mutation hotspots seen in skin cancers, thus explaining a key phenomenon in whole-genome cancer analyses.
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| 9. |
- Fredriksson, Nils Johan, 1979-, et al.
(author)
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Recurrent promoter mutations in melanoma are defined by an extended context-specific mutational signature
- 2017
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In: Plos Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 13:5
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Journal article (peer-reviewed)abstract
- Sequencing of whole tumor genomes holds the promise of revealing functional somatic regulatory mutations, such as those described in the TERT promoter. Recurrent promoter mutations have been identified in many additional genes and appear to be particularly common in melanoma, but convincing functional data such as influence on gene expression has been more elusive. Here, we show that frequently recurring promoter mutations in melanoma occur almost exclusively at cytosines flanked by a distinct sequence signature, TTCCG, with TERT as a notable exception. In active, but not inactive, promoters, mutation frequencies for cytosines at the 5' end of this ETS-like motif were considerably higher than expected based on a UV trinucleotide mutational signature. Additional analyses solidify this pattern as an extended context-specific mutational signature that mediates an exceptional position-specific vulnerability to UV mutagenesis, arguing against positive selection. We further use ultra-sensitive amplicon sequencing to demonstrate that cell cultures exposed to UV light quickly develop subclonal mutations specifically in affected positions. Our findings have implications for the interpretation of somatic mutations in regulatory regions, and underscore the importance of genomic context and extended sequence patterns to accurately describe mutational signatures in cancer.
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| 10. |
- Gabre, Jonatan L., 1988, et al.
(author)
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Preclinical exploration of the DNA damage response pathway using the interactive neuroblastoma cell line explorer CLEAN
- 2024
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In: NAR Cancer. - 2632-8674. ; 6:1
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Journal article (peer-reviewed)abstract
- Neuroblastoma (NB) is the most common cancer in infancy with an urgent need for more efficient targeted therapies. The development of novel (combinatorial) treatment strategies relies on extensive explorations of signaling perturbations in neuroblastoma cell lines, using RNA-Seq or other high throughput technologies (e.g. phosphoproteomics). This typically requires dedicated bioinformatics support, which is not always available. Additionally, while data from published studies are highly valuable and raw data (e.g. fastq files) are nowadays released in public repositories, data processing is time-consuming and again difficult without bioinformatics support. To facilitate NB research, more user-friendly and immediately accessible platforms are needed to explore newly generated as well as existing high throughput data. To make this possible, we developed an interactive data centralization and visualization web application, called CLEAN (the Cell Line Explorer web Application of Neuroblastoma data; https://ccgg.ugent.be/shiny/clean/). By focusing on the regulation of the DNA damage response, a therapeutic target of major interest in neuroblastoma, we demonstrate how CLEAN can be used to gain novel mechanistic insights and identify putative drug targets in neuroblastoma.
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| 11. |
- Guan, Jikui, et al.
(author)
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Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib.
- 2018
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In: Cold Spring Harbor molecular case studies. - : Cold Spring Harbor Laboratory. - 2373-2873. ; 4:4
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Journal article (peer-reviewed)abstract
- Tumors with Anaplastic Lymphoma Kinase (ALK) fusion rearrangements, including non-small cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors (TKIs), underscoring the notion that such cancers are addicted to ALK activity. While mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, due to lack of therapeutic options. Here we report a child with underlying FA and ALK mutant high-risk neuroblastoma responding strongly to precision therapy with the ALK TKI ceritinib. Conventional chemotherapy treatment caused severe, life-threatening toxicity. Genomic analysis of the initial biopsy identified germ-line FANCA mutations as well as a novel ALK-I1171T variant. ALK-I1171T generates a potent gain-of-function mutant, as measured in PC12 cell neurite outgrowth and NIH3T3 transformation. Pharmacological inhibition profiling of ALK-I1171T in response to various ALK TKIs identified an 11-fold improved inhibition of ALK-I1171T with ceritinib when compared with crizotinib. Immunoaffinity-coupled LC-MS/MS phosphoproteomics analysis indicated a decrease in ALK signaling in response to ceritinib. Ceritinib was therefore selected for treatment in this child. Mono-therapy with ceritinib was well tolerated and resulted in normalized catecholamine markers and tumor shrinkage. After 7.5 months treatment, residual primary tumor was surgically removed and exhibited hallmarks of differentiation together with reduced Ki67 levels. Clinical follow-up after 21 months treatment revealed complete clinical remission including all metastatic sites. Therefore, ceritinib presents a viable therapeutic option for ALK-positive neuroblastoma.
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| 12. |
- Serviss, J. T., et al.
(author)
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An antisense RNA capable of modulating the expression of the tumor suppressor microRNA-34a
- 2018
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In: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 9:7
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Journal article (peer-reviewed)abstract
- The microRNA-34a is a well-studied tumor suppressor microRNA (miRNA) and a direct downstream target of TP53 with roles in several pathways associated with oncogenesis, such as proliferation, cellular growth, and differentiation. Due to its broad tumor suppressive activity, it is not surprising that miR34a expression is altered in a wide variety of solid tumors and hematological malignancies. However, the mechanisms by which miR34a is regulated in these cancers is largely unknown. In this study, we find that a long noncoding RNA transcribed antisense to the miR34a host gene, is critical for miR34a expression and mediation of its cellular functions in multiple types of human cancer. We name this long noncoding RNA lncTAM34a, and characterize its ability to facilitate miR34a expression under different types of cellular stress in both TP53-deficient and wild-type settings.
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| 13. |
- Siaw, Joachim T., et al.
(author)
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11q Deletion or ALK Activity Curbs DLG2 Expression to Maintain an Undifferentiated State in Neuroblastoma
- 2020
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In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 32:12
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Journal article (peer-reviewed)abstract
- High-risk neuroblastomas typically display an undifferentiated or poorly differentiated morphology. It is therefore vital to understand molecular mechanisms that block the differentiation process. We identify an important role for oncogenic ALK-ERK1/2-SP1 signaling in the maintenance of undifferentiated neural crest-derived progenitors through the repression of DLG2, a candidate tumor suppressor gene in neuroblastoma. DLG2 is expressed in the murine "bridge signature'' that represents the transcriptional transition state when neural crest cells or Schwann cell precursors differentiate to chromaffin cells of the adrenal gland. We show that the restoration of DLG2 expression spontaneously drives neuroblastoma cell differentiation, high-lighting the importance of DLG2 in this process. These findings are supported by genetic analyses of high-risk 11q deletion neuroblastomas, which identified genetic lesions in the DLG2 gene. Our data also suggest that further exploration of other bridge genes may help elucidate the mechanisms underlying the differentiation of NC-derived progenitors and their contribution to neuroblastomas.
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| 14. |
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| 15. |
- Van den Eynden, Jimmy, 1977, et al.
(author)
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Lack of detectable neoantigen depletion signals in the untreated cancer genome.
- 2019
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 51:12, s. 1741-1748
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Journal article (peer-reviewed)abstract
- Somatic mutations can result in the formation of neoantigens, immunogenic peptides that are presented on the tumor cell surface by HLA molecules. These mutations are expected to be under negative selection pressure, but the extent of the resulting neoantigen depletion remains unclear. On the basis of HLA affinity predictions, we annotated the human genome for its translatability to HLA binding peptides and screened for reduced single nucleotide substitution rates in large genomic data sets from untreated cancers. Apparent neoantigen depletion signals become negligible when taking into consideration trinucleotide-based mutational signatures, owing to lack of power or to efficient immune evasion mechanisms that are active early during tumor evolution.
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| 16. |
- Van den Eynden, Jimmy, 1977, et al.
(author)
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Mutational signatures are critical for proper estimation of purifying selection pressures in cancer somatic mutation data when using the dN/dS metric
- 2017
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In: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 8:JUN
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Journal article (peer-reviewed)abstract
- Large cancer genome sequencing initiatives have led to the identification of cancer driver genes based on signals of positive selection in somatic mutation data. Additionally, the identification of purifying (negative) selection has the potential to identify essential genes that may be of therapeutic interest. The most widely used way of quantifying selection pressures in protein-coding genes is the dN/dS metric, which compares non-synonymous to synonymous substitution rates. In this study, we examine whether and how this metric is influenced by the mutational processes that have been active during tumor evolution. We use exome sequencing data from six different cancer types from The Cancer Genome Atlas (TCGA) and demonstrate that dN/dS in its basic form, where uniform base substitution probabilities are assumed, is in fact strongly biased by these mutational processes. This is particularly true in malignant melanoma, where the mutational signature is characterized by a high amount of UV-induced cytosine to thymine mutations at dipyrimidine dinucleotides. This increases the likelihood of random synonymous mutations occurring in hydrophobic amino acid codons, leading to reduced dN/dS ratios in genes encoding membrane proteins and falsely suggesting purifying selection in these genes. When this effect is corrected for by taking mutational signature-derived substitution probabilities into account, purifying selection was found to be limited and similar in all cancer types studied. Our results demonstrate that it is crucial to take mutational signatures into account when applying the dN/dS metric to cancer somatic mutation data. © 2017 Van den Eynden and Larsson.
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| 17. |
- Van den Eynden, Jimmy, 1977, et al.
(author)
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Phosphoproteome and gene expression profiling of ALK inhibition in neuroblastoma cell lines reveals conserved oncogenic pathways.
- 2018
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In: Science signaling. - : American Association for the Advancement of Science (AAAS). - 1937-9145 .- 1945-0877. ; 11:557
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Journal article (peer-reviewed)abstract
- Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that is a clinical target of major interest in cancer. Mutations and rearrangements in ALK trigger the activation of the encoded receptor and its downstream signaling pathways. ALK mutations have been identified in both familial and sporadic neuroblastoma cases as well as in 30 to 40% of relapses, which makes ALK a bona fide target in neuroblastoma therapy. Tyrosine kinase inhibitors (TKIs) that target ALK are currently in clinical use for the treatment of patients with ALK-positive non-small cell lung cancer. However, monotherapy with the ALK inhibitor crizotinib has been less encouraging in neuroblastoma patients with ALK alterations, raising the question of whether combinatorial therapy would be more effective. In this study, we established both phosphoproteomic and gene expression profiles of ALK activity in neuroblastoma cells exposed to first- and third-generation ALK TKIs, to identify the underlying molecular mechanisms and identify relevant biomarkers, signaling networks, and new therapeutic targets. This analysis has unveiled various important leads for novel combinatorial treatment strategies for patients with neuroblastoma and an increased understanding of ALK signaling involved in this disease.
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| 18. |
- Van den Eynden, Jimmy, 1977, et al.
(author)
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Somatic Mutation Patterns in Hemizygous Genomic Regions Unveil Purifying Selection during Tumor Evolution
- 2016
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In: Plos Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 27:12
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Journal article (peer-reviewed)abstract
- Identification of cancer driver genes using somatic mutation patterns indicative of positive selection has become a major goal in cancer genomics. However, cancer cells additionally depend on a large number of genes involved in basic cellular processes. While such genes should in theory be subject to strong purifying (negative) selection against damaging somatic mutations, these patterns have been elusive and purifying selection remains inadequately explored in cancer. Here, we hypothesized that purifying selection should be evident in hemizygous genomic regions, where damaging mutations cannot be compensated for by healthy alleles. Using a 7,781-sample pan-cancer dataset, we first confirmed this in POLR2A, an essential gene where hemizygous deletions are known to confer elevated sensitivity to pharmacological suppression. We next used this principle to identify several genes and pathways that show patterns indicative of purifying selection to avoid deleterious mutations. These include the POLR2A interacting protein INTS10 as well as genes involved in mRNA splicing, nonsense-mediated mRNA decay and other RNA processing pathways. Many of these genes belong to large protein complexes, and strong overlaps were observed with recent functional screens for gene essentiality in human cells. Our analysis supports that purifying selection acts to preserve the remaining function of many hemizygously deleted essential genes in tumors, indicating vulnerabilities that might be exploited by future therapeutic strategies.
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