Publications by authors named "David Tw Jones"

6 Publications

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A case series of Diffuse Glioneuronal Tumours with Oligodendroglioma-like features and Nuclear Clusters (DGONC).

Neuropathol Appl Neurobiol 2020 Dec 15. Epub 2020 Dec 15.

Developmental Biology and Cancer (DBC) Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.

In this study, we report three paediatric cases of Diffuse Glioneuronal Tumours with Oligodendroglioma-like features and Nuclear Clusters (DGONC).
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http://dx.doi.org/10.1111/nan.12680DOI Listing
December 2020

Drivers underpinning the malignant transformation of giant cell tumour of bone.

J Pathol 2020 Dec 6;252(4):433-440. Epub 2020 Oct 6.

Department of Pathology (research), University College London Cancer Institute, London, UK.

The rare benign giant cell tumour of bone (GCTB) is defined by an almost unique mutation in the H3.3 family of histone genes H3-3A or H3-3B; however, the same mutation is occasionally found in primary malignant bone tumours which share many features with the benign variant. Moreover, lung metastases can occur despite the absence of malignant histological features in either the primary or metastatic lesions. Herein we investigated the genetic events of 17 GCTBs including benign and malignant variants and the methylation profiles of 122 bone tumour samples including GCTBs. Benign GCTBs possessed few somatic alterations and no other known drivers besides the H3.3 mutation, whereas all malignant tumours harboured at least one additional driver mutation and exhibited genomic features resembling osteosarcomas, including high mutational burden, additional driver event(s), and a high degree of aneuploidy. The H3.3 mutation was found to predate the development of aneuploidy. In contrast to osteosarcomas, malignant H3.3-mutated tumours were enriched for a variety of alterations involving TERT, other than amplification, suggesting telomere dysfunction in the transformation of benign to malignant GCTB. DNA sequencing of the benign metastasising GCTB revealed no additional driver alterations; polyclonal seeding in the lung was identified, implying that the metastatic lesions represent an embolic event. Unsupervised clustering of DNA methylation profiles revealed that malignant H3.3-mutated tumours are distinct from their benign counterpart, and other bone tumours. Differential methylation analysis identified CCND1, encoding cyclin D1, as a plausible cancer driver gene in these tumours because hypermethylation of the CCND1 promoter was specific for GCTBs. We report here the genomic and methylation patterns underlying the rare clinical phenomena of benign metastasising and malignant transformation of GCTB and show how the combination of genomic and epigenomic findings could potentially distinguish benign from malignant GCTBs, thereby predicting aggressive behaviour in challenging diagnostic cases. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5537DOI Listing
December 2020

Endometrial stromal sarcomas with BCOR-rearrangement harbor MDM2 amplifications.

J Pathol Clin Res 2020 07 30;6(3):178-184. Epub 2020 Apr 30.

Department of Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Recently a novel subtype of endometrial stromal sarcoma (ESS) defined by recurrent genomic alterations involving BCOR has been described (HGESS-BCOR). We identified a case of HGESS-BCOR with a ZC3H7B-BCOR gene fusion, which harbored an amplification of the MDM2 locus. This index case prompted us to investigate MDM2 amplification in four additional cases of HGESS-BCOR. Tumors were analyzed for MDM2 amplification by array-based profiling of copy number alterations (CNAs) and fluorescence in situ hybridization (FISH), as well as for MDM2 expression by immunohistochemistry (IHC). Additionally, a cohort of other mesenchymal uterine neoplasms, including 17 low-grade ESS, 6 classical high-grade ESS with YWHAE-rearrangement, 16 uterine tumors resembling ovarian sex cord tumors, 7 uterine leiomyomas and 8 uterine leiomyosarcomas, was analyzed for CNAs in MDM2. Copy number profiling identified amplification of the 12q15 region involving the MDM2 locus in all five HGESS-BCOR. Subsequent validation analyses of three tumors confirmed MDM2 amplification using MDM2 FISH. Accordingly, IHC showed MDM2 overexpression in all analyzed cases. None of the other uterine neoplasms in our series, including tumors that are in the histopathological differential diagnoses of HGESS-BCOR, showed copy number gains of MDM2. Together, our results indicate that HGESS-BCOR carries MDM2 amplifications, which has diagnostic implications and could potentially be used for targeted therapies in these clinically aggressive tumors.
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http://dx.doi.org/10.1002/cjp2.165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339170PMC
July 2020

EGFL7 enhances surface expression of integrin αβ to promote angiogenesis in malignant brain tumors.

EMBO Mol Med 2018 09;10(9)

Molecular Signal Transduction Laboratories, Institute for Microscopic Anatomy and Neurobiology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn), University Medical Center of the Johannes Gutenberg University, Mainz, Germany

Glioblastoma (GBM) is a typically lethal type of brain tumor with a median survival of 15 months postdiagnosis. This negative prognosis prompted the exploration of alternative treatment options. In particular, the reliance of GBM on angiogenesis triggered the development of anti-VEGF (vascular endothelial growth factor) blocking antibodies such as bevacizumab. Although its application in human GBM only increased progression-free periods but did not improve overall survival, physicians and researchers still utilize this treatment option due to the lack of adequate alternatives. In an attempt to improve the efficacy of anti-VEGF treatment, we explored the role of the gene in malignant glioma. We found that the encoded extracellular matrix protein epidermal growth factor-like protein 7 (EGFL7) was secreted by glioma blood vessels but not glioma cells themselves, while no major role could be assigned to the parasitic miRNAs miR-126/126*. EGFL7 expression promoted glioma growth in experimental glioma models and stimulated tumor vascularization. Mechanistically, this was mediated by an upregulation of integrin αβ on the cellular surface of endothelial cells, which enhanced fibronectin-induced angiogenic sprouting. Glioma blood vessels that formed were more mature as determined by pericyte and smooth muscle cell coverage. Furthermore, these vessels were less leaky as measured by magnetic resonance imaging of extravasating contrast agent. EGFL7-inhibition using a specific blocking antibody reduced the vascularization of experimental gliomas and increased the life span of treated animals, in particular in combination with anti-VEGF and the chemotherapeutic agent temozolomide. Data allow for the conclusion that this combinatorial regimen may serve as a novel treatment option for GBM.
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http://dx.doi.org/10.15252/emmm.201708420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127886PMC
September 2018

Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants.

Nat Commun 2018 06 18;9(1):2378. Epub 2018 Jun 18.

Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.

Soft tissue tumors of infancy encompass an overlapping spectrum of diseases that pose unique diagnostic and clinical challenges. We studied genomes and transcriptomes of cryptogenic congenital mesoblastic nephroma (CMN), and extended our findings to five anatomically or histologically related soft tissue tumors: infantile fibrosarcoma (IFS), nephroblastomatosis, Wilms tumor, malignant rhabdoid tumor, and clear cell sarcoma of the kidney. A key finding is recurrent mutation of EGFR in CMN by internal tandem duplication of the kinase domain, thus delineating CMN from other childhood renal tumors. Furthermore, we identify BRAF intragenic rearrangements in CMN and IFS. Collectively these findings reveal novel diagnostic markers and therapeutic strategies and highlight a prominent role of isolated intragenic rearrangements as drivers of infant tumors.
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http://dx.doi.org/10.1038/s41467-018-04650-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006309PMC
June 2018

FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma.

EMBO J 2016 10 13;35(20):2192-2212. Epub 2016 Sep 13.

Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden

SOX9 is a master transcription factor that regulates development and stem cell programs. However, its potential oncogenic activity and regulatory mechanisms that control SOX9 protein stability are poorly understood. Here, we show that SOX9 is a substrate of FBW7, a tumor suppressor, and a SCF (SKP1/CUL1/F-box)-type ubiquitin ligase. FBW7 recognizes a conserved degron surrounding threonine 236 (T236) in SOX9 that is phosphorylated by GSK3 kinase and consequently degraded by SCF Failure to degrade SOX9 promotes migration, metastasis, and treatment resistance in medulloblastoma, one of the most common childhood brain tumors. FBW7 is either mutated or downregulated in medulloblastoma, and in cases where FBW7 mRNA levels are low, SOX9 protein is significantly elevated and this phenotype is associated with metastasis at diagnosis and poor patient outcome. Transcriptional profiling of medulloblastoma cells expressing a degradation-resistant SOX9 mutant reveals activation of pro-metastatic genes and genes linked to cisplatin resistance. Finally, we show that pharmacological inhibition of PI3K/AKT/mTOR pathway activity destabilizes SOX9 in a GSK3/FBW7-dependent manner, rendering medulloblastoma cells sensitive to cytostatic treatment.
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http://dx.doi.org/10.15252/embj.201693889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069553PMC
October 2016