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  • 1
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i135-i135
    Description: Therapies for medulloblastoma, a highly malignant pediatric brain tumor, often impose debilitating effects on the developing child, highlighting the need for molecularly targeted treatments with reduced toxicity. Therapies aimed at tumor-intrinsic mechanisms have translated to limited success thus far. More effective therapeutic strategies may also need to target elements of the tumor microenvironment. Current understanding about the medulloblastoma microenvironment is limited, particularly its cellular composition. To identify genes and biomarkers that compose the medulloblastoma microenvironment, we performed whole-transcriptome sequencing and bioinformatics analyses of 16 patient-derived orthotopic medulloblastoma xenografts (PDOXs), comprising all four medulloblastoma subgroups and matching primary tumors, as well as early and late passages for some models. PDOXs were generated by intracranial injection of human tumor cells into the brain of NSG-mice. In PDOXs, mouse stroma supports human cancer cells. Therefore, the transcriptome of PDXs is composed of a mixture of human RNAs (deriving from tumor cells) and mouse RNAs (deriving from stroma) and a species-specific alignment approach allows for the simultaneous study of both tumor and microenvironment specific signals. The majority of genes differentially expressed between the primary tumors and PDOXs are significantly down-regulated in the human fraction of PDOX RNA-seq data, while being expressed in the mouse fraction, confirming that the human stroma is replaced by murine stromal cells. As additional proof-of-concept, these down-regulated genes are highly enriched for immune response-related genes and collagens. Expression of various growth factor genes, for example IGF2, known to play a role in medulloblastoma tumorigenesis, appears to be of stromal origin.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    Language: English
    In: Cancer Research, 07/01/2018, Vol.78(13 Supplement), pp.3172-3172
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 3
    Language: English
    In: Cancer Research, 07/01/2018, Vol.78(13 Supplement), pp.4124-4124
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 4
    Language: English
    In: Nature, 2018, Vol.555, pp.321-327
    Description: Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials
    ISSN: 0028-0836
    ISSN: 1476-4687
    Source: NARCIS (National Academic Research and Collaborations Information System)
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  • 5
  • 6
    Language: English
    In: Nature, July 2018, Vol.559(7714), pp.E10
    Description: In this Article, author Benedikt Brors was erroneously associated with affiliation number '8' (Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee, USA); the author's two other affiliations (affiliations '3' and '7', both at the German Cancer Research Center (DKFZ)) were correct. This has been corrected online.
    Keywords: Cancer ; Medical Schools;
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 7
    In: International Journal of Cancer, 15 June 2016, Vol.138(12), pp.2905-2914
    Description: Chromothripsis is a recently discovered form of genomic instability, characterized by tens to hundreds of clustered DNA rearrangements resulting from a single dramatic event. Telomere dysfunction has been suggested to play a role in the initiation of this phenomenon, which occurs in a large number of tumor entities. Here, we show that telomere attrition can indeed lead to catastrophic genomic events, and that telomere patterns differ between cells analyzed before and after such genomic catastrophes. Telomere length and telomere stabilization mechanisms diverge between samples with and without chromothripsis in a given tumor subtype. Longitudinal analyses of the evolution of chromothriptic patterns identify either stable patterns between matched primary and relapsed tumors, or loss of the chromothriptic clone in the relapsed specimen. The absence of additional chromothriptic events occurring between the initial tumor and the relapsed tumor sample points to telomere stabilization after the initial chromothriptic event which prevents further shattering of the genome. What's new? Chromothripsis is characterized by extensive locally clustered genomic rearrangements, whereby chromosome shattering is followed by rejoining of the DNA fragments by error‐prone repair mechanisms. The present study elaborates on a previously proposed role in the initiation of chromothripsis for telomere erosion and breakage‐fusion‐bridge (BFB) cycles, in which chromosomes repeatedly break and are rejoined. In cells lacking normal mechanisms for genome preservation, telomere attrition and BFB cycles induced chromothripsis. Subsequent activation of tumor‐specific telomere maintenance mechanisms prevented further chromosomal shattering. The findings suggest that telomere maintenance pathways may represent therapeutic targets in chromothripsis‐positive tumors.
    Keywords: Telomere ; Chromothripsis ; Genome Instability ; Genomic Catastrophe
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 8
    Language: English
    In: Nature medicine, November 2018, Vol.24(11), pp.1752-1761
    Description: Brain tumors are the leading cause of cancer-related death in children. Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors that may lead to novel therapeutic strategies. To evaluate new treatments, better preclinical models adequately reflecting the biological heterogeneity are needed. Through the Children's Oncology Group ACNS02B3 study, we have generated and comprehensively characterized 30 patient-derived orthotopic xenograft models and seven cell lines representing 14 molecular subgroups of pediatric brain tumors. Patient-derived orthotopic xenograft models were found to be representative of the human tumors they were derived from in terms of histology, immunohistochemistry, gene expression, DNA methylation, copy number, and mutational profiles. In vivo drug sensitivity of targeted therapeutics was associated with distinct molecular tumor subgroups and specific genetic alterations. These models and their molecular characterization provide an unprecedented resource for the cancer community to study key oncogenic drivers and to evaluate novel treatment strategies.
    Keywords: Biological Specimen Banks ; Immunohistochemistry ; Brain Neoplasms -- Pathology ; Xenograft Model Antitumor Assays -- Methods
    ISSN: 10788956
    E-ISSN: 1546-170X
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  • 9
    In: Nature, 2018
    Description: Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.
    Keywords: Sciences (General) ; Physics;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 10
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i70-i70
    Description: Embryonal Tumors with Multilayered Rosettes (ETMRs) are aggressive pediatric brain tumors mainly occurring in infants. In order to develop alternative treatment strategies for this deadly disease there is an urgent need for better understanding the mechanisms driving these tumors. We therefore analyzed a cohort of 60 ETMRs using whole genome and panel sequencing, DNA methylation, mRNA expression profiling, and miRNA sequencing. The genetic hallmark of ETMRs is amplification of miRNA cluster C19MC fused to TTYH1 present in ~90% of all ETMRs. ETMRs lacking the C19MC amplification are biologically highly similar to tumors with C19MC amplification, indicating that they do not represent a distinct subgroup. DNA sequencing revealed germline mutations affecting DNA repair genes or miRNA processing genes in a subset of cases, while tumor specific mutations included genes involved in the TP53-, SHH- WNT-, or miRNA processing pathways. Prevalence of mutations in miRNA processing pathways are specifically high in tumors without C19MC amplification, however overall recurrence of mutations is low within our cohort. We also detect high recurrence of genomic instability shown by pluriploidy, large abundance of CNVs, highly upregulated DNA repair pathways and chromothripsis primarily centered around the C19MC amplicon. Structural variations throughout the genome, including the C19MC amplicon, are highly conserved from primary tumor to relapse while other mutations show low conservation. These results suggest ETMR is an entity driven by structural variations rather than single nucleotide variants and could lead to new treatment options, specifically targeting genomic instability, to be tested in preclinical model systems of ETMR.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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