Publications by authors named "Andrew S Moore"

50 Publications

Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer.

Nat Med 2020 11 5;26(11):1742-1753. Epub 2020 Oct 5.

Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, Australia.

The Zero Childhood Cancer Program is a precision medicine program to benefit children with poor-outcome, rare, relapsed or refractory cancer. Using tumor and germline whole genome sequencing (WGS) and RNA sequencing (RNAseq) across 252 tumors from high-risk pediatric patients with cancer, we identified 968 reportable molecular aberrations (39.9% in WGS and RNAseq, 35.1% in WGS only and 25.0% in RNAseq only). Of these patients, 93.7% had at least one germline or somatic aberration, 71.4% had therapeutic targets and 5.2% had a change in diagnosis. WGS identified pathogenic cancer-predisposing variants in 16.2% of patients. In 76 central nervous system tumors, methylome analysis confirmed diagnosis in 71.1% of patients and contributed to a change of diagnosis in two patients (2.6%). To date, 43 patients have received a recommended therapy, 38 of whom could be evaluated, with 31% showing objective evidence of clinical benefit. Comprehensive molecular profiling resolved the molecular basis of virtually all high-risk cancers, leading to clinical benefit in some patients.
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http://dx.doi.org/10.1038/s41591-020-1072-4DOI Listing
November 2020

Actin chromobody imaging reveals sub-organellar actin dynamics.

Nat Methods 2020 09 10;17(9):917-921. Epub 2020 Aug 10.

Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies, La Jolla, CA, USA.

The actin cytoskeleton plays multiple critical roles in cells, from cell migration to organelle dynamics. The small and transient actin structures regulating organelle dynamics are challenging to detect with fluorescence microscopy, making it difficult to determine whether actin filaments are directly associated with specific membranes. To address these limitations, we developed fluorescent-protein-tagged actin nanobodies, termed 'actin chromobodies' (ACs), targeted to organelle membranes to enable high-resolution imaging of sub-organellar actin dynamics.
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http://dx.doi.org/10.1038/s41592-020-0926-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746311PMC
September 2020

Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma.

Cell Rep Med 2020 Jun;1(3)

Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada.

Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.
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http://dx.doi.org/10.1016/j.xcrm.2020.100038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394286PMC
June 2020

Quizartinib-resistant FLT3-ITD acute myeloid leukemia cells are sensitive to the FLT3-Aurora kinase inhibitor CCT241736.

Blood Adv 2020 04;4(7):1478-1491

Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, Sutton, United Kingdom.

Internal tandem duplication of FLT3 (FLT3-ITD) is one of the most common somatic mutations in acute myeloid leukemia (AML); it causes constitutive activation of FLT3 kinase and is associated with high relapse rates and poor survival. Small-molecule inhibition of FLT3 represents an attractive therapeutic strategy for this subtype of AML, although resistance from secondary FLT3 tyrosine kinase domain (FLT3-TKD) mutations is an emerging clinical problem. CCT241736 is an orally bioavailable, selective, and potent dual inhibitor of FLT3 and Aurora kinases. FLT3-ITD+ cells with secondary FLT3-TKD mutations have high in vitro relative resistance to the FLT3 inhibitors quizartinib and sorafenib, but not to CCT241736. The mechanism of action of CCT241736 results in significant in vivo efficacy, with inhibition of tumor growth observed in efficacy studies in FLT3-ITD and FLT3-ITD-TKD human tumor xenograft models. The efficacy of CCT241736 was also confirmed in primary samples from AML patients, including those with quizartinib-resistant disease, which induces apoptosis through inhibition of both FLT3 and Aurora kinases. The unique combination of CCT241736 properties based on robust potency, dual selectivity, and significant in vivo activity indicate that CCT241736 is a bona fide clinical drug candidate for FLT3-ITD and TKD AML patients with resistance to current drugs.
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http://dx.doi.org/10.1182/bloodadvances.2019000986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160287PMC
April 2020

Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes.

Authors:
Matthew Clarke Alan Mackay Britta Ismer Jessica C Pickles Ruth G Tatevossian Scott Newman Tejus A Bale Iris Stoler Elisa Izquierdo Sara Temelso Diana M Carvalho Valeria Molinari Anna Burford Louise Howell Alex Virasami Amy R Fairchild Aimee Avery Jane Chalker Mark Kristiansen Kelly Haupfear James D Dalton Wilda Orisme Ji Wen Michael Hubank Kathreena M Kurian Catherine Rowe Mellissa Maybury Stephen Crosier Jeffrey Knipstein Ulrich Schüller Uwe Kordes David E Kram Matija Snuderl Leslie Bridges Andrew J Martin Lawrence J Doey Safa Al-Sarraj Christopher Chandler Bassel Zebian Claire Cairns Rachael Natrajan Jessica K R Boult Simon P Robinson Martin Sill Ira J Dunkel Stephen W Gilheeney Marc K Rosenblum Debbie Hughes Paula Z Proszek Tobey J Macdonald Matthias Preusser Christine Haberler Irene Slavc Roger Packer Ho-Keung Ng Shani Caspi Mara Popović Barbara Faganel Kotnik Matthew D Wood Lissa Baird Monika Ashok Davare David A Solomon Thale Kristin Olsen Petter Brandal Michael Farrell Jane B Cryan Michael Capra Michael Karremann Jens Schittenhelm Martin U Schuhmann Martin Ebinger Winand N M Dinjens Kornelius Kerl Simone Hettmer Torsten Pietsch Felipe Andreiuolo Pablo Hernáiz Driever Andrey Korshunov Lotte Hiddingh Barbara C Worst Dominik Sturm Marc Zuckermann Olaf Witt Tabitha Bloom Clare Mitchell Evelina Miele Giovanna Stefania Colafati Francesca Diomedi-Camassei Simon Bailey Andrew S Moore Timothy E G Hassall Stephen P Lowis Maria Tsoli Mark J Cowley David S Ziegler Matthias A Karajannis Kristian Aquilina Darren R Hargrave Fernando Carceller Lynley V Marshall Andreas von Deimling Christof M Kramm Stefan M Pfister Felix Sahm Suzanne J Baker Angela Mastronuzzi Andrea Carai Maria Vinci David Capper Sergey Popov David W Ellison Thomas S Jacques David T W Jones Chris Jones

Cancer Discov 2020 Jul 1;10(7):942-963. Epub 2020 Apr 1.

Division of Molecular Pathology, Institute of Cancer Research, London, United Kingdom.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ( = 31), ( = 21), ( = 9), and ( = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of , or gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype...
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http://dx.doi.org/10.1158/2159-8290.CD-19-1030DOI Listing
July 2020

Erratum: deletion drives acute myeloid leukemia resistance to MEK inhibitors.

Oncotarget 2020 Jan 21;11(3):305. Epub 2020 Jan 21.

The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Australia.

[This corrects the article DOI: 10.18632/oncotarget.27206.].
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http://dx.doi.org/10.18632/oncotarget.27402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980628PMC
January 2020

Outcome of children relapsing after first allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia: a retrospective I-BFM analysis of 333 children.

Br J Haematol 2020 05 3;189(4):745-750. Epub 2020 Feb 3.

Division of Pediatric Hematology and Oncology, Department of Pediatrics, Universities of Medical University Hannover, Hannover, Germany.

Outcome of 333 children with acute myeloid leukaemia relapsing after a first allogeneic haematopoietic stem cell transplantation was analyzed. Four-year probability of overall survival (4y-pOS) was 14%. 4y-pOS for 122 children receiving a second haematopoietic stem cell transplantation was 31% and 3% for those that did not (P = <0·0001). Achievement of a subsequent remission impacted survival (P = <0·0001). For patients receiving a second transplant survival with or without achieving a subsequent remission was comparable. Graft source (bone marrow vs. peripheral blood stem cells, P = 0·046) and donor choice (matched family vs. matched unrelated donor, P = 0·029) positively impacted survival after relapse. Disease recurrence and non-relapse mortality at four years reached 45% and 22%.
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http://dx.doi.org/10.1111/bjh.16441DOI Listing
May 2020

The incidence of childhood cancer in Australia, 1983-2015, and projections to 2035.

Med J Aust 2020 02 26;212(3):113-120. Epub 2019 Dec 26.

Cancer Council Queensland, Brisbane, QLD.

Objectives: To describe changes in childhood cancer incidence in Australia, 1983-2015, and to estimate projected incidence to 2035.

Design, Setting: Population-based study; analysis of Australian Childhood Cancer Registry data for the 20 547 children under 15 years of age diagnosed with cancer in Australia between 1983 and 2015.

Main Outcome Measures: Incidence rate changes during 1983-2015 were assessed by joinpoint regression, with rates age-standardised to the 2001 Australian standard population. Incidence projections to 2035 were estimated by age-period-cohort modelling.

Results: The overall age-standardised incidence rate of childhood cancer increased by 34% between 1983 and 2015, increasing by 1.2% (95% CI, +0.5% to +1.9%) per annum between 2005 and 2015. During 2011-2015, the mean annual number of children diagnosed with cancer in Australia was 770, an incidence rate of 174 cases (95% CI, 169-180 cases) per million children per year. The incidence of hepatoblastoma (annual percentage change [APC], +2.3%; 95% CI, +0.8% to +3.8%), Burkitt lymphoma (APC, +1.6%; 95% CI, +0.4% to +2.8%), osteosarcoma (APC, +1.1%; 95%, +0.0% to +2.3%), intracranial and intraspinal embryonal tumours (APC, +0.9%; 95% CI, +0.4% to +1.5%), and lymphoid leukaemia (APC, +0.5%; 95% CI, +0.2% to +0.8%) increased significantly across the period 1983-2015. The incidence rate of childhood melanoma fell sharply between 1996 and 2015 (APC, -7.7%; 95% CI, -10% to -4.8%). The overall annual cancer incidence rate is conservatively projected to rise to about 186 cases (95% CI, 175-197 cases) per million children by 2035 (1060 cases per year).

Conclusions: The incidence rates of several childhood cancer types steadily increased during 1983-2015. Although the reasons for these rises are largely unknown, our findings provide a foundation for health service planning for meeting the needs of children who will be diagnosed with cancer until 2035.
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http://dx.doi.org/10.5694/mja2.50456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065138PMC
February 2020

Second primary cancers in people who had cancer as children: an Australian Childhood Cancer Registry population-based study.

Med J Aust 2020 02 19;212(3):121-125. Epub 2019 Nov 19.

Cancer Council Queensland, Brisbane, QLD.

Objective: To investigate the incidence of second primary cancers in people diagnosed with cancer during childhood.

Design, Setting: Retrospective, population-based study; analysis of Australian Childhood Cancer Registry data.

Participants: People alive at least two months after being diagnosed before the age of 15 years with a primary cancer, 1983-2013, followed until 31 December 2015 (2-33 years' follow-up).

Main Outcome Measures: Risks of second primary cancer compared with the general population, expressed as standardised incidence ratios (SIRs).

Results: Among 18 230 people diagnosed with cancer during childhood, 388 (2%) were later diagnosed with second primary cancers; the estimated 30-year cumulative incidence of second cancers was 4.4% (95% CI, 3.8-5.0%). The risk of a new primary cancer was five times as high as for the general population (SIR, 5.13; 95% CI, 4.65-5.67). Relative risk of a second primary cancer was greatest for people who had childhood rhabdomyosarcoma (SIR, 19.9; 95% CI, 14.4-27.6). Relative risk was particularly high for children who had undergone both chemotherapy and radiotherapy (SIR, 9.80; 95% CI, 8.35-11.5). Relative risk peaked during the 5 years following the first diagnosis (2 to less than 5 years: SIR, 10.3; 95% CI, 8.20-13.0), but was still significant at 20-33 years (SIR, 2.58; 95% CI, 2.02-3.30). The most frequent second primary cancers were thyroid carcinomas (65 of 388, 17%) and acute myeloid leukaemias (57, 15%).

Conclusions: Survivors of childhood cancer remain at increased risk of a second primary cancer well into adulthood. As the late effects of cancer treatment probably contribute to this risk, treatments need to be refined and their toxicity reduced, without reducing their benefit for survival.
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http://dx.doi.org/10.5694/mja2.50425DOI Listing
February 2020

deletion drives acute myeloid leukemia resistance to MEK inhibitors.

Oncotarget 2019 Oct 8;10(56):5755-5767. Epub 2019 Oct 8.

The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Australia.

Kinases such as MEK are attractive targets for novel therapy in cancer, including acute myeloid leukaemia (AML). Acquired and inherent resistance to kinase inhibitors, however, is becoming an increasingly important challenge for the clinical success of such therapeutics, and often arises from mutations in the drug-binding domain of the target kinase. To identify possible causes of resistance to MEK inhibition, we generated a model of resistance by long-term treatment of AML cells with AZD6244 (selumetinib). Remarkably, resistance to MEK inhibition was due to acquired haploinsufficiency, rather than mutation of MEK. Resistance via this mechanism was confirmed using CRISPR/Cas9 technology targeting exon 5 of . While loss has been previously implicated in resistance to a number of other therapeutic agents, this is the first time that it has been shown directly and in AML.
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http://dx.doi.org/10.18632/oncotarget.27206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791388PMC
October 2019

Invasive fungal infections in children with acute lymphoblastic leukaemia: Results from four Australian centres, 2003-2013.

Pediatr Blood Cancer 2019 10 16;66(10):e27915. Epub 2019 Jul 16.

NHMRC National Centre for Infections in Cancer, Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.

Background: Invasive fungal infections (IFI) are an important complication of acute lymphoblastic leukaemia (ALL) treatment. Our study describes the prevalence and outcomes of IFI in children with ALL.

Methods: IFI episodes in children with primary or relapsed ALL, identified for The Epidemiology and Risk Factors for Invasive Fungal Infections in Immunocompromised Children study, were analysed. IFI were classified according to European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group criteria with a 'modified-possible' category included.

Results: A total of 123 IFI episodes in 119 patients with ALL were included. A proven, probable, possible and modified-possible IFI was diagnosed in 56 (45.5%), 22 (17.9%), 39 (31.7%) and six (4.9%) episodes, respectively. The prevalence was 9.7% (95% confidence interval [CI] 8-11.4%) overall and 23.5% (95% CI 14.5-32.5%) for relapsed/refractory ALL. For non-relapsed ALL, the IFI prevalence was significantly higher for children with high-risk compared to standard-risk ALL (14.5% vs 7.3%, P = .009), and IFI were more common during induction, consolidation and delayed intensification phases. Mould infections occurred more frequently than non-mould infections. Thirteen children (10.9%) died within 6 months of IFI diagnosis with five deaths (4.2%) attributable to an IFI.

Conclusions: IFI is more common in children with high-risk ALL and in relapsed disease. Overall survival was encouraging, with IFI contributing to very few deaths.
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http://dx.doi.org/10.1002/pbc.27915DOI Listing
October 2019

Hematopoietic stem cell transplantation for children with acute myeloid leukemia in second remission: A report from the Australasian Bone Marrow Transplant Recipient Registry and the Australian and New Zealand Children's Haematology Oncology Group.

Pediatr Blood Cancer 2019 08 20;66(8):e27812. Epub 2019 May 20.

The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia.

Background: Approximately one-third of children with acute myeloid leukemia (AML) relapse, requiring re-treatment and allogeneic hematopoietic stem cell transplantation (HSCT). Although achieving second complete remission (CR2) prior to HSCT is desirable, once CR2 is attained, it is unclear if there is any benefit from further chemotherapy prior to HSCT. Moreover, although pre-HSCT minimal residual disease (MRD) has prognostic value in acute lymphoblastic leukemia, the benefit of MRD reduction after achieving CR prior to HSCT is less clear for AML.

Procedure: To address these questions, we analyzed data from pediatric transplant centers in Australia and New Zealand concerning relapsed childhood AML cases occurring between 1998 and 2013. Given the retrospective nature of our analysis and assay data available, we analyzed patients on the basis of measurable residual disease (MeRD) by any methodology, rather than MRD in the conventional sense.

Results: We observed improved overall survival (OS) in children receiving two chemotherapy cycles, compared to one cycle or three or more cycles pre-HSCT. Improved OS with two cycles remained significant for patients without MeRD after cycle 1.

Conclusions: These data suggest that a second chemotherapy cycle pre-HSCT may improve survival by lowering disease burden. Prospective trials assessing strategies to reduce pre-HSCT MRD in relapsed childhood AML are warranted.
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http://dx.doi.org/10.1002/pbc.27812DOI Listing
August 2019

ALK2 inhibitors display beneficial effects in preclinical models of mutant diffuse intrinsic pontine glioma.

Commun Biol 2019 9;2:156. Epub 2019 May 9.

1Divisions of Molecular Pathology, The Institute of Cancer Research, London, SM2 5NG UK.

Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in , encoding the serine/threonine kinase ALK2. Despite being an amenable drug target, little has been done to-date to systematically evaluate the role of in DIPG, nor to screen currently available inhibitors in patient-derived tumour models. Here we show the dependence of DIPG cells on the mutant receptor, and the preclinical efficacy of two distinct chemotypes of ALK2 inhibitor in vitro and in vivo. We demonstrate the pyrazolo[1,5-a]pyrimidine LDN-193189 and the pyridine LDN-214117 to be orally bioavailable and well-tolerated, with good brain penetration. Treatment of immunodeprived mice bearing orthotopic xenografts of H3.3K27M, R206H mutant HSJD-DIPG-007 cells with 25 mg/kg LDN-193189 or LDN-214117 for 28 days extended survival compared with vehicle controls. Development of ALK2 inhibitors with improved potency, selectivity and advantageous pharmacokinetic properties may play an important role in therapy for DIPG patients.
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http://dx.doi.org/10.1038/s42003-019-0420-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509210PMC
April 2020

Stage at diagnosis for children with blood cancers in Australia: Application of the Toronto Paediatric Cancer Stage Guidelines in a population-based national childhood cancer registry.

Pediatr Blood Cancer 2019 06 25;66(6):e27683. Epub 2019 Feb 25.

Cancer Council Queensland, Brisbane, Queensland, Australia.

Background: Information on stage at diagnosis for childhood blood cancers is essential for surveillance but is not available on a population basis in most countries. Our aim was to apply the internationally endorsed Toronto Paediatric Cancer Stage Guidelines to children (<15 years) with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), or non-Hodgkin lymphoma (NHL) and to assess differences in survival by stage at diagnosis.

Procedure: Stage was defined by extent of involvement of the central nervous system (CNS) for ALL and AML and using the Ann Arbor and St Jude-Murphy systems for HL and NHL, respectively. The study cohort was drawn from the population-based Australian Childhood Cancer Registry, consisting of children diagnosed with one of these four blood cancers between 2006 and 2014 with follow-up to 2015. Five-year observed survival was estimated from the Kaplan-Meier method.

Results: Stage was assigned to 2201 of 2351 eligible patients (94%), ranging from 85% for AML to 95% for ALL, HL, and NHL. Survival following ALL varied from 94% (95% CI = 93%-95%) for CNS1 disease to 89% (95% CI = 79%-94%) for CNS2 (P = 0.07), whereas for AML there was essentially no difference in survival between CNS (77%) and CNS disease (78%; P = 0.94). Nearly all children with HL survived for five years. There was a trend (P = 0.04) toward worsening survival with higher stage for NHL.

Conclusions: These results provide the first population-wide picture of the distribution and outcomes for childhood blood cancers in Australia by extent of disease at diagnosis and provide a baseline for future comparisons.
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http://dx.doi.org/10.1002/pbc.27683DOI Listing
June 2019

Imaging the Dynamics of Mitophagy in Live Cells.

Methods Mol Biol 2019 ;1880:601-610

Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Investigating the precise spatiotemporal dynamics of mitophagy can provide insights into how mitochondrial quality control is regulated in different tissues and organisms. Here, we outline live imaging assays to quantitatively assess mitophagy dynamics in real time. This protocol describes both chemical and optogenetic techniques to induce mitochondrial damage with high spatial and temporal control. Using these assays, mitochondria can be tracked from before they sustain damage up to their engulfment by autophagosomes and acidification by lysosomes.
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http://dx.doi.org/10.1007/978-1-4939-8873-0_39DOI Listing
June 2019

Mitochondrial-cytoskeletal interactions: dynamic associations that facilitate network function and remodeling.

Curr Opin Physiol 2018 Jun 7;3:94-100. Epub 2018 Apr 7.

Department of Physiology, University of Pennsylvania Perelman School of Medicine 638A Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104-6085.

Mitochondria are dynamic organelles that can form complex networks in the cell. These networks can be rapidly remodeled in response to environmental changes or to support cellular needs. Mitochondrial dynamics are dependent on interactions with the cellular cytoskeleton - both microtubules and actin filaments. Mitochondrial-cytoskeletal interactions have a well-established role in mitochondrial motility. Recent progress indicates that these interactions also regulate the balance of mitochondrial fission/fusion, as well as mitochondria turnover and mitochondrial inheritance during cell division. We review these advances, and how this work has deepened our understanding of mitochondrial dynamics in the cell.
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http://dx.doi.org/10.1016/j.cophys.2018.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289269PMC
June 2018

Epidemiology of invasive fungal infections in immunocompromised children; an Australian national 10-year review.

Pediatr Blood Cancer 2019 04 4;66(4):e27564. Epub 2018 Dec 4.

Lady Cilento Children's Hospital, Children's Health Queensland, South Brisbane, Australia.

Background: A thorough understanding of local and contemporary invasive fungal infection (IFI) epidemiology in immunocompromised children is required to provide a rationale for targeted prevention and treatment strategies.

Methods: Retrospective data over 10 years from four tertiary pediatric oncology and hematopoietic stem cell transplant (HSCT) units across Australia were analyzed to report demographic, clinical, and mycological characteristics of IFI episodes, and crude IFI prevalence in select oncology/HSCT groups. Kaplan-Meier survival analyses were used to calculate 180-day overall survival.

Results: A total of 337 IFI episodes occurred in 320 children, of which 149 (44.2%), 51 (15.1%), and 110 (32.6%) met a modified European Organization for Research and Treatment of Cancer (mEORTC) criteria for proven, probable, and possible IFI, respectively. There were a further 27 (8.0%) that met a "modified possible IFI" criteria. Median age at IFI diagnosis was 8.4 years. Crude mEORTC IFI prevalence in acute lymphoblastic leukemia, acute myeloid leukemia, solid tumor, and allogeneic HSCT cohorts was 10.6%, 28.2%, 4.4%, and 11.7%, respectively. Non-Aspergillus species represented 48/102 (47.1%) molds identified, and non-albicans Candida represented 66/93 (71.0%) yeasts identified. There were 56 deaths among 297 children who met mEORTC criteria, with 180-day overall survival for proven, probable, and possible IFIs of 79.7%, 76.2%, and 84.4%, respectively.

Conclusion: Non-Aspergillus molds and non-albicans Candida contributed substantially to pediatric IFI in our study, with high IFI prevalence in leukemia and allogeneic HSCT cohorts. Inclusion of IFIs outside of European Organization for Research and Treatment of Cancer criteria revealed an IFI burden that would go otherwise unrecognized in published reports.
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http://dx.doi.org/10.1002/pbc.27564DOI Listing
April 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.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, 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

Therapy-related acute myeloid leukemia following treatment for cancer in childhood: A population-based registry study.

Pediatr Blood Cancer 2018 12 5;65(12):e27410. Epub 2018 Sep 5.

Oncology Services Group, Children's Health Queensland Hospital and Health Service, Brisbane, Australia.

Background: Therapy-related acute myeloid leukemia (t-AML) is defined as AML that develops after exposure to cytotoxic chemotherapy and/or radiation therapy. There is a paucity of available literature, particularly in regard to t-AML following childhood cancer. Our aim was to describe the risk of t-AML among children treated for other cancers and their subsequent survival.

Procedure: We utilized data from the population-based Australian Childhood Cancer Registry to examine all childhood patients (<15 years at diagnosis) treated with chemotherapy and/or radiotherapy for cancers other than AML who received a subsequent diagnosis of AML between 1983 and 2014. Standardized incidence ratios (SIRs) were calculated to approximate the relative risk of being diagnosed with AML compared to the general population. Estimates of 5-year observed survival were obtained using the Kaplan-Meier method, with differences determined by the log-rank test.

Results: Fifty-eight of 11,753 patients in the study cohort (0.5%) were diagnosed with t-AML, an almost 50-fold higher risk than expected (SIR = 45.6, 95% confidence interval [CI] = 35.3-59.0). Five-year observed survival from the date of t-AML diagnosis was 31.2% (95% CI = 19.6-43.5%). A significant survival advantage was found for patients who underwent hematopoietic stem cell transplantation (HSCT) following diagnosis of t-AML, with a 5-year survival of 52.4% (29.7-70.9%) compared to 5.7% (0.4-22.6%) for those who did not have HSCT (P < 0.001).

Conclusions: Although rare, t-AML is an important potential late effect of childhood cancer therapy. Prognosis is generally poor, with HSCT offering some survival benefit.
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http://dx.doi.org/10.1002/pbc.27410DOI Listing
December 2018

Assessing the feasibility and validity of the Toronto Childhood Cancer Stage Guidelines: a population-based registry study.

Lancet Child Adolesc Health 2018 03 1;2(3):173-179. Epub 2018 Feb 1.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MD, USA.

Background: Cancer stage at diagnosis is crucial for assessing global efforts to increase awareness of childhood cancer and improve outcomes. However, consistent information on childhood cancer stage is absent from population cancer registries worldwide. The Toronto Childhood Cancer Stage Guidelines, compiled through an international consensus process, were designed to provide a standard framework for collection of information on stage at diagnosis of childhood cancers. We aimed to assess the feasibility of implementing the Toronto Guidelines within a national population cancer registry.

Methods: We did a population-based registry study using data from the Australian Childhood Cancer Registry and included data from children aged 0-14 years diagnosed between Jan 1, 2006, and Dec 31, 2010 with one of 16 childhood cancers listed in the Toronto Guidelines (acute lymphoblastic leukaemia, acute myeloid leukaemia, Hodgkin's lymphoma, non-Hodgkin lymphoma, neuroblastoma, Wilms' tumour, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma, osteosarcoma, Ewing's sarcoma, retinoblastoma, hepatoblastoma, testicular cancer, ovarian cancer, medulloblastoma, and ependymoma). We extracted data from medical records, and assigned stage according to the Tier 1 criteria (basic) and Tier 2 criteria (more detailed, requiring data from cytology, imaging, and other diagnostic tests, where available) using computer algorithms derived from the Toronto Guidelines. Additionally, expert reviewers independently assigned Tier 2 stage to a random subsample of 160 cases (ten per malignancy type). Feasibility of the guidelines was assessed on the percentage of cases that could be staged, agreement between stage assigned by the algorithms and the expert reviewers, and the mean time (min) taken to collect the required data.

Findings: We obtained data for 1412 eligible children. Stage could be assigned according to Tier 2 criteria for 1318 (93%) cases, ranging from 48 (84%) of 57 cases of non-rhabdomyosarcoma soft tissue sarcoma to 46 (100%) cases of hepatoblastoma. According to Tier 1 criteria, stage could be assigned for 1329 (94%) cases, ranging from 131 (87%) of 151 cases of acute myeloid leukaemia to 46 (100%) cases of hepatoblastoma. By contrast, stage at diagnosis was recorded by the treating physician for 555 (39%) of the 1412 cases. The computer algorithm assigned the same stage as did one or more independent expert reviewers in 155 (97%) of the 160 cases assessed. The mean time taken to review medical records and extract the required data was 18·0 min (SD 9·5 per case).

Interpretation: The Toronto Guidelines provide a highly functional framework that can be used to assign cancer stage at diagnosis using data routinely available in medical records for most childhood cancers. Data on staging have the potential to inform interventions targeting improved diagnosis and survival.

Funding: Cancer Australia.
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http://dx.doi.org/10.1016/S2352-4642(18)30023-3DOI Listing
March 2018

Functional diversity and cooperativity between subclonal populations of pediatric glioblastoma and diffuse intrinsic pontine glioma cells.

Nat Med 2018 08 2;24(8):1204-1215. Epub 2018 Jul 2.

Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.

The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments.
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http://dx.doi.org/10.1038/s41591-018-0086-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086334PMC
August 2018

Molecular Minimal Residual Disease Monitoring in Acute Myeloid Leukemia: Challenges and Future Directions.

J Mol Diagn 2018 07 22;20(4):389-397. Epub 2018 Apr 22.

The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia; Oncology Services Group, Children's Health Queensland Hospital and Health Service, Brisbane, Australia; UQ Child Health Research Centre, The University of Queensland, Brisbane, Australia. Electronic address:

The ability to sensitively monitor minimal residual disease (MRD) has played a key role in improving the management and outcomes for a number of leukemias, particularly acute promyelocytic leukemia and childhood acute lymphoblastic leukemia. By contrast, MRD monitoring in acute myeloid leukemia (AML) has been limited by variable assay methodologies and a relative paucity of patient-specific MRD markers. Inter- and intratumor genetic heterogeneity poses significant challenges for the identification of molecular markers suitable for MRD monitoring in AML, particularly for those cases without structural chromosomal rearrangements associated with fusion genes. Furthermore, the need to discriminate which mutations may be suitable for MRD monitoring creates additional complexity. The mainstay of current molecular MRD monitoring is real-time quantitative PCR, targeting fusion genes, mutations, and gene overexpression. New technologies, particularly next-generation sequencing approaches, offer new ways to overcome these limitations. Here, the authors review the techniques available for molecular MRD monitoring in AML and discuss their utility in clinical practice.
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http://dx.doi.org/10.1016/j.jmoldx.2018.03.005DOI Listing
July 2018

The ten-year evolutionary trajectory of a highly recurrent paediatric high grade neuroepithelial tumour with MN1:BEND2 fusion.

Sci Rep 2018 01 18;8(1):1032. Epub 2018 Jan 18.

Centre for Evolution and Cancer, Institute of Cancer Research, London, UK.

Astroblastomas are rare brain tumours which predominate in children and young adults, and have a controversial claim as a distinct entity, with no established WHO grade. Reports suggest a better outcome than high grade gliomas, though they frequently recur. Recently, they have been described to overlap with a newly-discovered group of tumours described as'high grade neuroepithelial tumour with MN1 alteration' (CNS HGNET-MN1), defined by global methylation patterns and strongly associated with gene fusions targeting MN1. We have studied a unique case of astroblastoma arising in a 6 year-old girl, with multiple recurrences over a period of 10 years, with the pathognomonic MN1:BEND2 fusion. Exome sequencing allowed for a phylogenetic reconstruction of tumour evolution, which when integrated with clinical, pathological and radiological data provide for a detailed understanding of disease progression, with initial treatment driving tumour dissemination along four distinct trajectories. Infiltration of distant sites was associated with a later genome doubling, whilst there was evidence of convergent evolution of different lesions acquiring distinct alterations targeting NF-κB. These data represent an unusual opportunity to understand the evolutionary history of a highly recurrent childhood brain tumour, and provide novel therapeutic targets for astroblastoma/CNS HGNET-MN1.
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http://dx.doi.org/10.1038/s41598-018-19389-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773598PMC
January 2018

Development of a targeted sequencing approach to identify prognostic, predictive and diagnostic markers in paediatric solid tumours.

Oncotarget 2017 Dec 6;8(67):112036-112050. Epub 2017 Dec 6.

Molecular Diagnostics Department, The Institute of Cancer Research and Clinical Genomics, The Royal Marsden NHS Foundation, London, United Kingdom.

The implementation of personalised medicine in childhood cancers has been limited by a lack of clinically validated multi-target sequencing approaches specific for paediatric solid tumours. In order to support innovative clinical trials in high-risk patients with unmet need, we have developed a clinically relevant targeted sequencing panel spanning 311 kb and comprising 78 genes involved in childhood cancers. A total of 132 samples were used for the validation of the panel, including Horizon Discovery cell blends (n=4), cell lines (n=15), formalin-fixed paraffin embedded (FFPE, n=83) and fresh frozen tissue (FF, n=30) patient samples. Cell blends containing known single nucleotide variants (SNVs, n=528) and small insertion-deletions (indels n=108) were used to define panel sensitivities of ≥98% for SNVs and ≥83% for indels [95% CI] and panel specificity of ≥98% [95% CI] for SNVs. FFPE samples performed comparably to FF samples (n=15 paired). Of 95 well-characterised genetic abnormalities in 33 clinical specimens and 13 cell lines (including SNVs, indels, amplifications, rearrangements and chromosome losses), 94 (98.9%) were detected by our approach. We have validated a robust and practical methodology to guide clinical management of children with solid tumours based on their molecular profiles. Our work demonstrates the value of targeted gene sequencing in the development of precision medicine strategies in paediatric oncology.
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http://dx.doi.org/10.18632/oncotarget.23000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762377PMC
December 2017

Targeted Next-Generation Sequencing for Detecting Gene Fusions in Leukemia.

Mol Cancer Res 2018 02 13;16(2):279-285. Epub 2017 Nov 13.

The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.

Mixed lineage leukemia () gene rearrangements characterize approximately 70% of infant and 10% of adult and therapy-related leukemia. Conventional clinical diagnostics, including cytogenetics and fluorescence hybridization (FISH) fail to detect translocation partner genes (TPG) in many patients. Long-distance inverse (LDI)-PCR, the "gold standard" technique that is used to characterize breakpoints, is laborious and requires a large input of genomic DNA (gDNA). To overcome the limitations of current techniques, a targeted next-generation sequencing (NGS) approach that requires low RNA input was tested. Anchored multiplex PCR-based enrichment (AMP-E) was used to rapidly identify a broad range of fusions in patient specimens. Libraries generated using Archer FusionPlex Heme and Myeloid panels were sequenced using the Illumina platform. Diagnostic specimens ( = 39) from pediatric leukemia patients were tested with AMP-E and validated by LDI-PCR. In concordance with LDI-PCR, the AMP-E method successfully identified TPGs without prior knowledge. AMP-E identified 10 different fusions in the 39 samples. Only two specimens were discordant; AMP-E successfully identified a fusion where LDI-PCR had failed to determine the breakpoint, whereas a fusion was not detected by AMP-E due to low expression of the fusion transcript. Sensitivity assays demonstrated that AMP-E can detect in MV4-11 cell dilutions of 10 and transcripts down to 0.005 copies/ng. This study demonstrates a NGS methodology with improved sensitivity compared with current diagnostic methods for -rearranged leukemia. Furthermore, this assay rapidly and reliably identifies partner genes and patient-specific fusion sequences that could be used for monitoring minimal residual disease. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0569DOI Listing
February 2018

Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.

Cancer Cell 2017 10 28;32(4):520-537.e5. Epub 2017 Sep 28.

Division of Molecular Pathology, The Institute of Cancer Research, London, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK. Electronic address:

We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.
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http://dx.doi.org/10.1016/j.ccell.2017.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637314PMC
October 2017

Differential expression of MUC4, GPR110 and IL2RA defines two groups of CRLF2-rearranged acute lymphoblastic leukemia patients with distinct secondary lesions.

Cancer Lett 2017 11 1;408:92-101. Epub 2017 Sep 1.

Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, SA, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia; Australian Genomic Health Alliance, Adelaide, SA, Australia. Electronic address:

CRLF2-rearrangements (CRLF2-r) occur frequently in Ph-like B-ALL, a high-risk ALL sub-type characterized by a signaling profile similar to Ph + ALL, however accumulating evidence indicates genetic heterogeneity within CRLF2-r ALL. We performed thorough genomic characterization of 35 CRLF2-r cases (P2RY8-CRLF2 n = 18; IGH-CRLF2 n = 17). Activating JAK2 mutations were present in 34% of patients, and a CRLF2-F232C mutation was identified in an additional 17%. IKZF1 deletions were detected in 63% of cases. The majority of patients (26/35) classified as Ph-like, and these were characterized by significantly higher levels of MUC4, GPR110 and IL2RA/CD25. In addition, Ph-like CRLF2-r samples were significantly enriched for IKZF1 deletions, JAK2/CRLF2 mutations and increased expression of JAK/STAT target genes (CISH, SOCS1), suggesting that mutation-driven CRLF2/JAK2 activation is more frequent in this sub-group. Less is known about the genomics of CRLF2-r cases lacking JAK2-pathway mutations, but KRAS/NRAS mutations were identified in 4/9 non-Ph-like samples. This work highlights the heterogeneity of secondary lesions which may arise and influence intracellular-pathway activation in CRLF2-r patients, and importantly presents distinct therapeutic targets within a group of patients harboring identical primary translocations, for whom efficient directed therapies are currently lacking.
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http://dx.doi.org/10.1016/j.canlet.2017.08.034DOI Listing
November 2017

Intertumoral Heterogeneity within Medulloblastoma Subgroups.

Authors:
Florence M G Cavalli Marc Remke Ladislav Rampasek John Peacock David J H Shih Betty Luu Livia Garzia Jonathon Torchia Carolina Nor A Sorana Morrissy Sameer Agnihotri Yuan Yao Thompson Claudia M Kuzan-Fischer Hamza Farooq Keren Isaev Craig Daniels Byung-Kyu Cho Seung-Ki Kim Kyu-Chang Wang Ji Yeoun Lee Wieslawa A Grajkowska Marta Perek-Polnik Alexandre Vasiljevic Cecile Faure-Conter Anne Jouvet Caterina Giannini Amulya A Nageswara Rao Kay Ka Wai Li Ho-Keung Ng Charles G Eberhart Ian F Pollack Ronald L Hamilton G Yancey Gillespie James M Olson Sarah Leary William A Weiss Boleslaw Lach Lola B Chambless Reid C Thompson Michael K Cooper Rajeev Vibhakar Peter Hauser Marie-Lise C van Veelen Johan M Kros Pim J French Young Shin Ra Toshihiro Kumabe Enrique López-Aguilar Karel Zitterbart Jaroslav Sterba Gaetano Finocchiaro Maura Massimino Erwin G Van Meir Satoru Osuka Tomoko Shofuda Almos Klekner Massimo Zollo Jeffrey R Leonard Joshua B Rubin Nada Jabado Steffen Albrecht Jaume Mora Timothy E Van Meter Shin Jung Andrew S Moore Andrew R Hallahan Jennifer A Chan Daniela P C Tirapelli Carlos G Carlotti Maryam Fouladi José Pimentel Claudia C Faria Ali G Saad Luca Massimi Linda M Liau Helen Wheeler Hideo Nakamura Samer K Elbabaa Mario Perezpeña-Diazconti Fernando Chico Ponce de León Shenandoah Robinson Michal Zapotocky Alvaro Lassaletta Annie Huang Cynthia E Hawkins Uri Tabori Eric Bouffet Ute Bartels Peter B Dirks James T Rutka Gary D Bader Jüri Reimand Anna Goldenberg Vijay Ramaswamy Michael D Taylor

Cancer Cell 2017 06;31(6):737-754.e6

The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada. Electronic address:

While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.
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http://dx.doi.org/10.1016/j.ccell.2017.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163053PMC
June 2017

Erratum to: Population pharmacokinetic modelling of doxorubicin and doxorubicinol in children with cancer: is there a relationship with cardiac troponin profiles?

Cancer Chemother Pharmacol 2017 07;80(1):27-28

Translational Research Institute, The University of Queensland Diamantina Institute, Brisbane, Australia.

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http://dx.doi.org/10.1007/s00280-017-3338-1DOI Listing
July 2017