Publications by authors named "Daniel Catchpoole"

80 Publications

Immuno-transcriptomic profiling of extracranial pediatric solid malignancies.

Cell Rep 2021 Nov;37(8):110047

University of Toronto Musculoskeletal Oncology Unit, Sinai Health System; Department of Surgery, University of Toronto, Toronto, ON, Canada.

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.
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http://dx.doi.org/10.1016/j.celrep.2021.110047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8642810PMC
November 2021

What Do Biomedical Researchers Want from Biobanks? Results of an Online Survey.

Biopreserv Biobank 2021 Nov 9. Epub 2021 Nov 9.

New South Wales Health Statewide Biobank, New South Wales Health Pathology, Camperdown, Australia.

The purpose of biobanking is to provide biospecimens and associated data to researchers, yet the perspectives of biobank research users have been under-investigated. This study aimed to ascertain biobank research users' needs and opinions about biobanking services. An online survey was developed, which requested information about researcher demographics, localities of biobanks accessed, methods of sourcing biospecimens, and opinions on topics including but not limited to, application processes, data availability, access fees, and return of research results. There were 27 multiple choice/check box questions, 4 questions with a 10-point Likert scale, and 8 questions with provision for further comment. A web link for the survey was distributed to researchers in late 2019/early 2020 in four Australian states: New South Wales, Victoria, Western Australia, and South Australia. Respondents were generally satisfied with biobank application processes and the fit for purpose of received biospecimens/data. Nonetheless, most researchers ( = 61/99, 62%) reported creating their own collections owing to gaps in sample availability and a perceived increase in efficiency. Most accessed biobanks ( = 58/74, 78%) were in close proximity (local or intrastate) to the researcher. Most researchers had limited the scope of their research owing to difficulty of obtaining biospecimens ( = 55/86, 64%) and/or data ( = 52/85, 60%), with the top three responses for additional types of data required being "more long term follow up data," "more clinical data," and "more linked government data." The top influence to use a particular biobank was cost, and the most frequently suggested improvement was reduced direct "cost of obtaining biospecimens." Biobanks that do not meet the needs of their end-users are unlikely to be optimally utilized or sustainable. This survey provides valuable insights to guide biobanks and other stakeholders, such as developing marketing and client engagement plans to encourage local research users and discouraging the creation of unnecessary new collections.
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http://dx.doi.org/10.1089/bio.2021.0084DOI Listing
November 2021

Rare germline variants in childhood cancer patients suspected of genetic predisposition to cancer.

Genes Chromosomes Cancer 2021 Oct 23. Epub 2021 Oct 23.

Molecular Oncology Laboratory, Children's Cancer Research Unit, Kids Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.

Identification of cancer-predisposing germline variants in childhood cancer patients is important for therapeutic decisions, disease surveillance and risk assessment for patients, and potentially, also for family members. We investigated the spectrum and prevalence of pathogenic germline variants in selected childhood cancer patients with features suggestive of genetic predisposition to cancer. Germline DNA was subjected to exome sequencing to filter variants in 1048 genes of interest including 176 known cancer predisposition genes (CPGs). An enrichment burden analysis compared rare deleterious germline CPG variants in the patient cohort with those in a healthy aged control population. A subset of predicted deleterious variants in novel candidate CPGs was investigated further by examining matched tumor samples, and the functional impact of AXIN1 variants was analyzed in cultured cells. Twenty-two pathogenic/likely pathogenic (P/LP) germline variants detected in 13 CPGs were identified in 19 of 76 patients (25.0%). Unclear association with the diagnosed cancer types was observed in 11 of 19 patients carrying P/LP CPG variants. The burden of rare deleterious germline variants in autosomal dominant CPGs was significantly higher in study patients versus healthy aged controls. A novel AXIN1 frameshift variant (Ser321fs) may impact the regulation of β-catenin levels. Selection of childhood cancer patients for germline testing based on features suggestive of an underlying genetic predisposition could help to identify carriers of clinically relevant germline CPG variants, and streamline the integration of germline genomic testing in the pediatric oncology clinic.
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http://dx.doi.org/10.1002/gcc.23006DOI Listing
October 2021

Pathogenic Germline Variants in Cancer Susceptibility Genes in Children and Young Adults With Rhabdomyosarcoma.

JCO Precis Oncol 2021 11;5. Epub 2021 Jan 11.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.

Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma and accounts for 3% of all pediatric cancer. In this study, we investigated germline sequence and structural variation in a broad set of genes in two large, independent RMS cohorts.

Materials And Methods: Genome sequencing of the discovery cohort (n = 273) and exome sequencing of the secondary cohort (n = 121) were conducted on germline DNA. Analyses were performed on 130 cancer susceptibility genes (CSG). Pathogenic or likely pathogenic (P/LP) variants were predicted using the American College of Medical Genetics and Genomics (ACMG) criteria. Structural variation and survival analyses were performed on the discovery cohort.

Results: We found that 6.6%-7.7% of patients with RMS harbored P/LP variants in dominant-acting CSG. An additional approximately 1% have structural variants (, ) in CSGs. CSG variants did not influence survival, although there was a significant correlation with an earlier age of tumor onset. There was a nonsignificant excess of P/LP variants in dominant inheritance genes in the patients with fusion-negative RMS patients versus the patients with fusion-positive RMS. We identified pathogenic germline variants in CSGs previously (, , , mismatch repair genes), rarely (, , , ), or never () reported in RMS. Numerous genes (, , mismatch repair) were on the ACMG Secondary Findings 2.0 list.

Conclusion: In two cohorts of patients with RMS, we identified pathogenic germline variants for which gene-specific therapies and surveillance guidelines may be beneficial. In families with a proband with an RMS-risk P/LP variant, genetic counseling and cascade testing should be considered, especially for ACMG Secondary Findings genes and/or with gene-specific surveillance guidelines.
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http://dx.doi.org/10.1200/PO.20.00218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169077PMC
January 2021

Special Issue on Biobanking for Pediatric Research.

Biopreserv Biobank 2021 04 26;19(2):97. Epub 2021 Mar 26.

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http://dx.doi.org/10.1089/bio.2021.29083.djcDOI Listing
April 2021

Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia.

Haematologica 2021 Feb 11. Epub 2021 Feb 11.

Kids Cancer Centre, Sydney Children's Hospital Randwick, Sydney, Australia; School of Women and Children's Health, University of New South Wales (UNSW), Sydney, Australia; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney.

Symptomatic methotrexate-related central neurotoxicity, 'MTX neurotoxicity', is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic complications. Risk factors and long-term outcomes require further study. We conducted a systematic, retrospective review of 1251 consecutive Australian children enrolled on BFM or COG-based protocols between 1998-2013. Clinical risk predictors for MTX neurotoxicity were analyzed using regression. A genome-wide association study (GWAS) was performed on 48 cases and 537 controls. The incidence of MTX neurotoxicity was 7.6% (n=95/1251), at a median of 4 months from ALL diagnosis and 8 days after intravenous or intrathecal MTX. Grade 3 elevation of serum aspartate aminotransferase (P=0.005, OR 2.31 (1.28-4.16)) in induction/consolidation was associated with MTX neurotoxicity, after accounting for the only established risk factor, age a10 years. Cumulative incidence of CNS relapse was increased in children where intrathecal MTX was omitted following symptomatic MTX neurotoxicity (n=48) compared to where intrathecal MTX was continued throughout therapy (n=1174) (P=0.047). Five-year CNS relapsefree survival was 89.2%±4.6% when intrathecal MTX was ceased compared to 95.4%±0.6% when intrathecal MTX was continued. Recurrence of MTX neurotoxicity was low (12.9%) for patients whose intrathecal MTX was continued after their first episode. The GWAS identified SNPs associated with MTX neurotoxicity near genes regulating neuronal growth, neuronal differentiation and cytoskeletal organization (P>1E-06). In conclusion, increased serum aspartate aminotransferase and age a10 years at diagnosis were independent risk factors for MTX neurotoxicity. Our data do not support cessation of intrathecal MTX after a first MTX neurotoxicity event.
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http://dx.doi.org/10.3324/haematol.2020.268565DOI Listing
February 2021

Transcriptomic Analyses of MYCN-Regulated Genes in Anaplastic Wilms' Tumour Cell Lines Reveals Oncogenic Pathways and Potential Therapeutic Vulnerabilities.

Cancers (Basel) 2021 Feb 6;13(4). Epub 2021 Feb 6.

Cancer Epigenetics Laboratory, School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK.

The proto-oncogene is deregulated in many cancers, most notably in neuroblastoma, where gene amplification identifies a clinical subset with very poor prognosis. Gene expression and DNA analyses have also demonstrated overexpression of mRNA, as well as focal amplifications, copy number gains and presumptive change of function mutations of in Wilms' tumours with poorer outcomes, including tumours with diffuse anaplasia. Surprisingly, however, the expression and functions of the MYCN protein in Wilms' tumours still remain obscure. In this study, we assessed MYCN protein expression in primary Wilms' tumours using immunohistochemistry of tissue microarrays. We found MYCN protein to be expressed in tumour blastemal cells, and absent in stromal and epithelial components. For functional studies, we used two anaplastic Wilms' tumour cell-lines, WiT49 and 17.94, to study the biological and transcriptomic effects of MYCN depletion. We found that MYCN knockdown consistently led to growth suppression but not cell death. RNA sequencing identified 561 MYCN-regulated genes shared by WiT49 and 17.94 cell-lines. As expected, numerous cellular processes were downstream of MYCN. MYCN positively regulated the miRNA regulator and known Wilms' tumour oncogene , the genes encoding methylosome proteins PRMT1, PRMT5 and WDR77, and the mitochondrial translocase genes and . MYCN repressed genes including the developmental signalling receptor and the stromal marker . Importantly, we found that MYCN also repressed the presumptive Wilms' tumour suppressor gene , with MYCN knockdown resulting in increased REST protein and concomitant repression of RE1-Silencing Transcription factor (REST) target genes. Together, our study identifies regulatory axes that interact with MYCN, providing novel pathways for potential targeted therapeutics for poor-prognosis Wilms' tumour.
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http://dx.doi.org/10.3390/cancers13040656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915280PMC
February 2021

Improving Academic Biobank Value and Sustainability Through an Outputs Focus.

Value Health 2020 08 2;23(8):1072-1078. Epub 2020 Aug 2.

NSW Health Statewide Biobank, NSW Health Pathology, Professor Marie Bashir Centre, Camperdown, NSW, Australia. Electronic address:

Although it is generally accepted that human tissue biobanks are important to facilitate progress in health and medical research, many academic biobanks face sustainability challenges. We propose that biobank sustainability is challenged by a lack of available data describing the outputs and benefits that are produced by biobanks, as reflected by a dearth of publications that enumerate biobank outputs. We further propose that boosting the available information on biobank outputs and using a broader range of output metrics will permit economic analyses such as cost-consequence analyses of biobank activity. Output metrics and cost-consequence analyses can allow biobanks to achieve efficiencies, and improve the quality and/or quantity of their outputs. In turn, biobank output measures provide all stakeholders with explicit and accountable data on biobank value, which could contribute to the evolution of biobank operations to best match research needs, and mitigate some threats to biobank sustainability.
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http://dx.doi.org/10.1016/j.jval.2020.05.010DOI Listing
August 2020

Pediatric Biobanking: Kids Are Not Just Little Adults.

Biopreserv Biobank 2020 Aug 20;18(4):258-265. Epub 2020 Jul 20.

Pathology, Phoenix Children's Hospital, Phoenix, Arizona, USA.

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http://dx.doi.org/10.1089/bio.2020.29071.djcDOI Listing
August 2020

Increased Efficacy of Histone Methyltransferase G9a Inhibitors Against -Amplified Neuroblastoma.

Front Oncol 2020 27;10:818. Epub 2020 May 27.

Cancer Epigenetics Laboratory, School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.

Targeted inhibition of proteins modulating epigenetic changes is an increasingly important priority in cancer therapeutics, and many small molecule inhibitors are currently being developed. In the case of neuroblastoma (NB), a pediatric solid tumor with a paucity of intragenic mutations, epigenetic deregulation may be especially important. In this study we validate the histone methyltransferase G9a/EHMT2 as being associated with indicators of poor prognosis in NB. Immunological analysis of G9a protein shows it to be more highly expressed in NB cell-lines with amplification, which is a primary determinant of dismal outcome in NB patients. Furthermore, G9a protein in primary tumors is expressed at higher levels in poorly differentiated/undifferentiated NB, and correlates with high EZH2 expression, a known co-operative oncoprotein in NB. Our functional analyses demonstrate that siRNA-mediated G9a depletion inhibits cell growth in all NB cell lines, but, strikingly, only triggers apoptosis in NB cells with amplification, suggesting a synthetic lethal relationship between G9a and MYCN. This pattern of sensitivity is also evident when using small molecule inhibitors of G9a, UNC0638, and UNC0642. The increased efficacy of G9a inhibition in the presence of MYCN-overexpression is also demonstrated in the SHEP-21N isogenic model with tet-regulatable MYCN. Finally, using RNA sequencing, we identify several potential tumor suppressor genes that are reactivated by G9a inhibition in NB, including the , and . Together, our study underlines the under-appreciated role of G9a in NB, especially in -amplified tumors.
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http://dx.doi.org/10.3389/fonc.2020.00818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269128PMC
May 2020

The "Federated Pediatric BioCloud" Model: State of the Art and Future Prospects in Pediatric Biospecimen Science.

J Pediatr 2020 06;221S:S43-S48

The Tumour Bank, Children's Cancer Research Unit, Kids Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia; The Faculty of Engineering and Information Technology, The University of Technology Sydney, Ultimo, New South Wales, Australia.

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http://dx.doi.org/10.1016/j.jpeds.2020.02.068DOI Listing
June 2020

Genome-Wide Association Meta-Analysis of Single-Nucleotide Polymorphisms and Symptomatic Venous Thromboembolism during Therapy for Acute Lymphoblastic Leukemia and Lymphoma in Caucasian Children.

Cancers (Basel) 2020 May 19;12(5). Epub 2020 May 19.

Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, 2100 Copenhagen, Denmark.

Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied.

Methods: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included.

Results: No SNPs reached genome-wide significance ( < 5 × 10) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) ( < 1 × 10), two loci had concordant effects in both cohorts: (rs1804772) (MAF: 1%; = 3.95 × 10) that influences arachidonic acid metabolism and thus platelet aggregation, and (rs570684) (MAF: 1%; = 4.34 × 10) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease.

Conclusion: This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.
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http://dx.doi.org/10.3390/cancers12051285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280960PMC
May 2020

Moving ISBER into the Future: Looking Beyond Our Horizons.

Biopreserv Biobank 2020 06 11;18(3):254-255. Epub 2020 May 11.

President Elect, ISBER.

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http://dx.doi.org/10.1089/bio.2020.29070.djcDOI Listing
June 2020

A Wnt-BMP4 Signaling Axis Induces MSX and NOTCH Proteins and Promotes Growth Suppression and Differentiation in Neuroblastoma.

Cells 2020 03 23;9(3). Epub 2020 Mar 23.

Cancer Epigenetics Laboratory, School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK.

The Wnt and bone morphogenetic protein (BMP) signaling pathways are known to be crucial in the development of neural crest lineages, including the sympathetic nervous system. Surprisingly, their role in paediatric neuroblastoma, the prototypic tumor arising from this lineage, remains relatively uncharacterised. We previously demonstrated that Wnt/b-catenin signaling can have cell-type-specific effects on neuroblastoma phenotypes, including growth inhibition and differentiation, and that BMP4 mRNA and protein were induced by Wnt3a/Rspo2. In this study, we characterised the phenotypic effects of BMP4 on neuroblastoma cells, demonstrating convergent induction of MSX homeobox transcription factors by Wnt and BMP4 signaling and BMP4-induced growth suppression and differentiation. An immunohistochemical analysis of BMP4 expression in primary neuroblastomas confirms a striking absence of BMP4 in poorly differentiated tumors, in contrast to a high expression in ganglion cells. These results are consistent with a tumor suppressive role for BMP4 in neuroblastoma. RNA sequencing following BMP4 treatment revealed induction of Notch signaling, verified by increases of Notch3 and Hes1 proteins. Together, our data demonstrate, for the first time, Wnt-BMP-Notch signaling crosstalk associated with growth suppression of neuroblastoma.
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http://dx.doi.org/10.3390/cells9030783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140810PMC
March 2020

Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: a Rare Brain Tumor Consortium registry study.

Acta Neuropathol 2020 02 9;139(2):223-241. Epub 2019 Dec 9.

The Institute of Cancer Research, London, UK.

Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC sub-group, respectively, characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.
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http://dx.doi.org/10.1007/s00401-019-02111-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673644PMC
February 2020

Non-Coding RNAs in Pediatric Solid Tumors.

Front Genet 2019 20;10:798. Epub 2019 Sep 20.

School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia.

Pediatric solid tumors are a diverse group of extracranial solid tumors representing approximately 40% of childhood cancers. Pediatric solid tumors are believed to arise as a result of disruptions in the developmental process of precursor cells which lead them to accumulate cancerous phenotypes. In contrast to many adult tumors, pediatric tumors typically feature a low number of genetic mutations in protein-coding genes which could explain the emergence of these phenotypes. It is likely that oncogenesis occurs after a failure at many different levels of regulation. Non-coding RNAs (ncRNAs) comprise a group of functional RNA molecules that lack protein coding potential but are essential in the regulation and maintenance of many epigenetic and post-translational mechanisms. Indeed, research has accumulated a large body of evidence implicating many ncRNAs in the regulation of well-established oncogenic networks. In this review we cover a range of extracranial solid tumors which represent some of the rarer and enigmatic childhood cancers known. We focus on two major classes of ncRNAs, microRNAs and long non-coding RNAs, which are likely to play a key role in the development of these cancers and emphasize their functional contributions and molecular interactions during tumor formation.
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http://dx.doi.org/10.3389/fgene.2019.00798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764412PMC
September 2019

A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor.

Cancer Cell 2019 07;36(1):51-67.e7

Children's Brain Tumor Research Centre, Queen's Medical Centre University of Nottingham, Nottingham NG72UH, UK.

Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death.
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http://dx.doi.org/10.1016/j.ccell.2019.06.002DOI Listing
July 2019

Biobank: What's in a Name?

Biopreserv Biobank 2019 Jun;17(3):204-208

5 Division of Anatomic Pathology, Department of Pathology, The University of Alabama at Birmingham (UAB), Birmingham, Alabama.

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http://dx.doi.org/10.1089/bio.2019.29053.mjbDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065495PMC
June 2019

Visual Analytics of Genomic and Cancer Data: A Systematic Review.

Cancer Inform 2019 13;18:1176935119835546. Epub 2019 Mar 13.

The Tumour Bank, Children's Cancer Research Unit, Kids Research, The Children's Hospital at Westmead, Westmead, NSW, Australia.

Visual analytics and visualisation can leverage the human perceptual system to interpret and uncover hidden patterns in big data. The advent of next-generation sequencing technologies has allowed the rapid production of massive amounts of genomic data and created a corresponding need for new tools and methods for visualising and interpreting these data. Visualising genomic data requires not only simply plotting of data but should also offer a decision or a choice about what the message should be conveyed in the particular plot; which methodologies should be used to represent the results must provide an easy, clear, and accurate way to the clinicians, experts, or researchers to interact with the data. Genomic data visual analytics is rapidly evolving in parallel with advances in high-throughput technologies such as artificial intelligence (AI) and virtual reality (VR). Personalised medicine requires new genomic visualisation tools, which can efficiently extract knowledge from the genomic data and speed up expert decisions about the best treatment of individual patient's needs. However, meaningful visual analytics of such large genomic data remains a serious challenge. This article provides a comprehensive systematic review and discussion on the tools, methods, and trends for visual analytics of cancer-related genomic data. We reviewed methods for genomic data visualisation including traditional approaches such as scatter plots, heatmaps, coordinates, and networks, as well as emerging technologies using AI and VR. We also demonstrate the development of genomic data visualisation tools over time and analyse the evolution of visualising genomic data.
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http://dx.doi.org/10.1177/1176935119835546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416684PMC
March 2019

ISBER's Global Outlook: A Summary of Recent International Activities.

Biopreserv Biobank 2019;17(1):91-92. Epub 2019 Jan 29.

5 International Agency for Research on Cancer (IARC), World Health Organization (WHO), Lyon, France.

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http://dx.doi.org/10.1089/bio.2019.29047.drcDOI Listing
June 2019

The genetic basis and cell of origin of mixed phenotype acute leukaemia.

Nature 2018 10 12;562(7727):373-379. Epub 2018 Sep 12.

Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Mixed phenotype acute leukaemia (MPAL) is a high-risk subtype of leukaemia with myeloid and lymphoid features, limited genetic characterization, and a lack of consensus regarding appropriate therapy. Here we show that the two principal subtypes of MPAL, T/myeloid (T/M) and B/myeloid (B/M), are genetically distinct. Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia. We show that the intratumoral immunophenotypic heterogeneity characteristic of MPAL is independent of somatic genetic variation, that founding lesions arise in primitive haematopoietic progenitors, and that individual phenotypic subpopulations can reconstitute the immunophenotypic diversity in vivo. These findings indicate that the cell of origin and founding lesions, rather than an accumulation of distinct genomic alterations, prime tumour cells for lineage promiscuity. Moreover, these findings position MPAL in the spectrum of immature leukaemias and provide a genetically informed framework for future clinical trials of potential treatments for MPAL.
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http://dx.doi.org/10.1038/s41586-018-0436-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195459PMC
October 2018

Computer Aided Classification of Neuroblastoma Histological Images Using Scale Invariant Feature Transform with Feature Encoding.

Diagnostics (Basel) 2018 Aug 28;8(3). Epub 2018 Aug 28.

Centre for Artificial Intelligence, Faculty of Engineering and Information Technology, University of Technology Sydney, Ultimo, NSW 2007, Australia.

Neuroblastoma is the most common extracranial solid malignancy in early childhood. Optimal management of neuroblastoma depends on many factors, including histopathological classification. Although histopathology study is considered the gold standard for classification of neuroblastoma histological images, computers can help to extract many more features some of which may not be recognizable by human eyes. This paper, proposes a combination of Scale Invariant Feature Transform with feature encoding algorithm to extract highly discriminative features. Then, distinctive image features are classified by Support Vector Machine classifier into five clinically relevant classes. The advantage of our model is extracting features which are more robust to scale variation compared to the Patched Completed Local Binary Pattern and Completed Local Binary Pattern methods. We gathered a database of 1043 histologic images of neuroblastic tumours classified into five subtypes. Our approach identified features that outperformed the state-of-the-art on both our neuroblastoma dataset and a benchmark breast cancer dataset. Our method shows promise for classification of neuroblastoma histological images.
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http://dx.doi.org/10.3390/diagnostics8030056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165255PMC
August 2018

Germline mutations and somatic inactivation of TRIM28 in Wilms tumour.

PLoS Genet 2018 06 18;14(6):e1007399. Epub 2018 Jun 18.

Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

Wilms tumour is a childhood tumour that arises as a consequence of somatic and rare germline mutations, the characterisation of which has refined our understanding of nephrogenesis and carcinogenesis. Here we report that germline loss of function mutations in TRIM28 predispose children to Wilms tumour. Loss of function of this transcriptional co-repressor, which has a role in nephrogenesis, has not previously been associated with cancer. Inactivation of TRIM28, either germline or somatic, occurred through inactivating mutations, loss of heterozygosity or epigenetic silencing. TRIM28-mutated tumours had a monomorphic epithelial histology that is uncommon for Wilms tumour. Critically, these tumours were negative for TRIM28 immunohistochemical staining whereas the epithelial component in normal tissue and other Wilms tumours stained positively. These data, together with a characteristic gene expression profile, suggest that inactivation of TRIM28 provides the molecular basis for defining a previously described subtype of Wilms tumour, that has early age of onset and excellent prognosis.
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http://dx.doi.org/10.1371/journal.pgen.1007399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005459PMC
June 2018

Convolutional Deep Belief Network with Feature Encoding for Classification of Neuroblastoma Histological Images.

J Pathol Inform 2018 2;9:17. Epub 2018 May 2.

Centre for Artificial Intelligence, Faculty of Engineering and Information Technology, University of Technology Sydney, NSW, Australia.

Background: Neuroblastoma is the most common extracranial solid tumor in children younger than 5 years old. Optimal management of neuroblastic tumors depends on many factors including histopathological classification. The gold standard for classification of neuroblastoma histological images is visual microscopic assessment. In this study, we propose and evaluate a deep learning approach to classify high-resolution digital images of neuroblastoma histology into five different classes determined by the Shimada classification.

Subjects And Methods: We apply a combination of convolutional deep belief network (CDBN) with feature encoding algorithm that automatically classifies digital images of neuroblastoma histology into five different classes. We design a three-layer CDBN to extract high-level features from neuroblastoma histological images and combine with a feature encoding model to extract features that are highly discriminative in the classification task. The extracted features are classified into five different classes using a support vector machine classifier.

Data: We constructed a dataset of 1043 neuroblastoma histological images derived from Aperio scanner from 125 patients representing different classes of neuroblastoma tumors.

Results: The weighted average F-measure of 86.01% was obtained from the selected high-level features, outperforming state-of-the-art methods.

Conclusion: The proposed computer-aided classification system, which uses the combination of deep architecture and feature encoding to learn high-level features, is highly effective in the classification of neuroblastoma histological images.
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http://dx.doi.org/10.4103/jpi.jpi_73_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952548PMC
May 2018

Clinically Relevant Cytotoxic Immune Cell Signatures and Clonal Expansion of T-Cell Receptors in High-Risk -Not-Amplified Human Neuroblastoma.

Clin Cancer Res 2018 11 21;24(22):5673-5684. Epub 2018 May 21.

Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

High-risk neuroblastoma is an aggressive disease. DNA sequencing studies have revealed a paucity of actionable genomic alterations and a low mutation burden, posing challenges to develop effective novel therapies. We used RNA sequencing (RNA-seq) to investigate the biology of this disease, including a focus on tumor-infiltrating lymphocytes (TIL). We performed deep RNA-seq on pretreatment diagnostic tumors from 129 high-risk and 21 low- or intermediate-risk patients with neuroblastomas. We used single-sample gene set enrichment analysis to detect gene expression signatures of TILs in tumors and examined their association with clinical and molecular parameters, including patient outcome. The expression profiles of 190 additional pretreatment diagnostic neuroblastomas, a neuroblastoma tissue microarray, and T-cell receptor (TCR) sequencing were used to validate our findings. We found that -not-amplified (-NA) tumors had significantly higher cytotoxic TIL signatures compared with -amplified (-A) tumors. A reported MYCN activation signature was significantly associated with poor outcome for high-risk patients with -NA tumors; however, a subgroup of these patients who had elevated activated natural killer (NK) cells, CD8 T cells, and cytolytic signatures showed improved outcome and expansion of infiltrating TCR clones. Furthermore, we observed upregulation of immune exhaustion marker genes, indicating an immune-suppressive microenvironment in these neuroblastomas. This study provides evidence that RNA signatures of cytotoxic TIL are associated with the presence of activated NK/T cells and improved outcomes in high-risk neuroblastoma patients harboring -NA tumors. Our findings suggest that these high-risk patients with -NA neuroblastoma may benefit from additional immunotherapies incorporated into the current therapeutic strategies. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504934PMC
November 2018

Wnt Signalling Drives Context-Dependent Differentiation or Proliferation in Neuroblastoma.

Neoplasia 2018 04 3;20(4):335-350. Epub 2018 Mar 3.

Cancer Epigenetics Laboratory, School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK. Electronic address:

Neuroblastoma is one of the commonest and deadliest solid tumours of childhood, and is thought to result from disrupted differentiation of the developing sympathoadrenergic lineage of the neural crest. Neuroblastoma exhibits intra- and intertumoural heterogeneity, with high risk tumours characterised by poor differentiation, which can be attributable to MYCN-mediated repression of genes involved in neuronal differentiation. MYCN is known to co-operate with oncogenic signalling pathways such as Alk, Akt and MEK/ERK signalling, and, together with c-MYC has been shown to be activated by Wnt signalling in various tissues. However, our previous work demonstrated that Wnt3a/Rspo2 treatment of some neuroblastoma cell lines can, paradoxically, decrease c-MYC and MYCN proteins. This prompted us to define the neuroblastoma-specific Wnt3a/Rspo2-driven transcriptome using RNA sequencing, and characterise the accompanying changes in cell biology. Here we report the identification of ninety Wnt target genes, and show that Wnt signalling is upstream of numerous transcription factors and signalling pathways in neuroblastoma. Using live-cell imaging, we show that Wnt signalling can drive differentiation of SK-N-BE(2)-C and SH-SY5Y cell-lines, but, conversely, proliferation of SK-N-AS cells. We show that cell-lines that differentiate show induction of pro-differentiation BMP4 and EPAS1 proteins, which is not apparent in the SK-N-AS cells. In contrast, SK-N-AS cells show increased CCND1, phosphorylated RB and E2F1 in response to Wnt3a/Rspo2, consistent with their proliferative response, and these proteins are not increased in differentiating lines. By meta-analysis of the expression of our 90 genes in primary tumour gene expression databases, we demonstrate discrete expression patterns of our Wnt genes in patient cohorts with different prognosis. Furthermore our analysis reveals interconnectivity within subsets of our Wnt genes, with one subset comprised of novel putative drivers of neuronal differentiation repressed by MYCN. Assessment of β-catenin immunohistochemistry shows high levels of β-catenin in tumours with better differentiation, further supporting a role for canonical Wnt signalling in neuroblastoma differentiation.
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http://dx.doi.org/10.1016/j.neo.2018.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909736PMC
April 2018

DBNorm: normalizing high-density oligonucleotide microarray data based on distributions.

BMC Bioinformatics 2017 Nov 29;18(1):527. Epub 2017 Nov 29.

School of Software, Faculty of Engineering and Information Technology and the Centre for Artificial Intelligence, University of Technology Sydney (UTS), PO Box 123, 15 Broadway, Ultimo, NSW, 2007, Australia.

Background: Data from patients with rare diseases is often produced using different platforms and probe sets because patients are widely distributed in space and time. Aggregating such data requires a method of normalization that makes patient records comparable.

Results: This paper proposed DBNorm, implemented as an R package, is an algorithm that normalizes arbitrarily distributed data to a common, comparable form. Specifically, DBNorm merges data distributions by fitting functions to each of them, and using the probability of each element drawn from the fitted distribution to merge it into a global distribution. DBNorm contains state-of-the-art fitting functions including Polynomial, Fourier and Gaussian distributions, and also allows users to define their own fitting functions if required.

Conclusions: The performance of DBNorm is compared with z-score, average difference, quantile normalization and ComBat on a set of datasets, including several that are publically available. The performance of these normalization methods are compared using statistics, visualization, and classification when class labels are known based on a number of self-generated and public microarray datasets. The experimental results show that DBNorm achieves better normalization results than conventional methods. Finally, the approach has the potential to be applicable outside bioinformatics analysis.
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http://dx.doi.org/10.1186/s12859-017-1912-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706403PMC
November 2017

Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors.

Cancer Cell 2016 Dec;30(6):891-908

Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.

We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.
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http://dx.doi.org/10.1016/j.ccell.2016.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500911PMC
December 2016
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