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| Open AccessDeleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8+ T cell adoptive therapies in pre-clinical studies
Treatment failure following chimaeric antigen receptor (CAR) T cell therapy is common yet incompletely understood. In this study, the authors demonstrate that deletion of the mitochondrial negative regulator, MCJ, in CAR T cells promotes target cell killing ex vivo and augments their efficacy in an in vivo B cell leukaemia model.
- Meng-Han Wu
- , Felipe Valenca-Pereira
- & Mercedes Rincon
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Article
| Open AccessWhole genome and transcriptome integrated analyses guide clinical care of pediatric poor prognosis cancers
Efforts to allow routine whole genome and transcriptome analysis (WGTA) for pediatric cancers in the clinic remain critical. Here, the authors present results of a unified genomics and bioinformatics pipeline for WGTA in paediatric cancers, the Personalized OncoGenomics (POG) program, with a focus on potential therapeutic targets.
- Rebecca J. Deyell
- , Yaoqing Shen
- & Shahrad R. Rassekh
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| Open AccessA human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations
Copy number alterations in stem cells impair neural crest differentiation and set the stage for neuroblastoma-like traits and tumours. This study hints at early tumourigenesis mechanisms and finds developmental gene signatures linked to prognosis.
- Ingrid M. Saldana-Guerrero
- , Luis F. Montano-Gutierrez
- & Florian Halbritter
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| Open AccessDiscovery of immunotherapy targets for pediatric solid and brain tumors by exon-level expression
CAR T cell immunotherapy for paediatric solid and brain tumours is constrained by the availability of targetable antigens. Here, the authors investigate the landscape of cancer-specific exons as potential targets by analysing 1,532 RNAseq datasets from 16 types of paediatric solid and brain tumours.
- Timothy I. Shaw
- , Jessica Wagner
- & Stephen Gottschalk
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| Open AccessIdentifying tumor type and cell type-specific gene expression alterations in pediatric central nervous system tumors
The molecular features of paediatric central nervous system (CNS) tumours are not fully understood, posing a challenge for targeted therapies. Here, the authors characterise paediatric CNS tumours using single-nucleus RNA-seq; they identify cell type populations associated with specific tumour types and with response to therapy.
- Min Kyung Lee
- , Nasim Azizgolshani
- & Brock C. Christensen
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| Open AccessAssociations in cell type-specific hydroxymethylation and transcriptional alterations of pediatric central nervous system tumors
Cell type-specific epigenomic alterations and heterogeneity in paediatric central nervous system (CNS) tumours remain underexplored. Here, the authors integrate bulk DNA cytosine modification data with bulk and single-nucleus RNA-sequencing to explore cell type-specific epigenomic alterations and gene regulation in paediatric CNS tumours.
- Min Kyung Lee
- , Nasim Azizgolshani
- & Brock C. Christensen
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Article
| Open AccessA case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID
Leukaemia development has been reported as an associated risk of haematopoietic stem cell gene therapy (HSPC-GT) using retroviral vectors in different diseases. Here, the authors show a case of T-cell acute lymphoid leukaemia in a patient with Adenosine Deaminase-deficient Severe Combined Immunodeficiency (ADA-SCID) treated with retroviral gene therapy.
- Daniela Cesana
- , Maria Pia Cicalese
- & Alessandro Aiuti
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Article
| Open AccessTargeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma
Targeting oncogenic ALK activity in neuroblastoma is an attractive therapeutic strategy but success has been limited by resistance to ALK inhibitors. Here, the authors identify loss of miR-1304-5p as a driver of ALK inhibitor resistance via regulation of NRAS, and therapeutically target this axis with the addition of a farnesyltransferase inhibitor in preclinical models of neuroblastoma.
- Perla Pucci
- , Liam C. Lee
- & Suzanne D. Turner
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Article
| Open AccessLineage specific transcription factor waves reprogram neuroblastoma from self-renewal to differentiation
This study identifies temporal and coordinately regulated cell-state-specific super-enhancers driving the expression of transcription factors that control circuits needed to switch neuroblastoma tumor cells from self-renewal to differentiation.
- Deblina Banerjee
- , Sukriti Bagchi
- & Carol J. Thiele
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Article
| Open AccessSingle-cell multiomics reveals the interplay of clonal evolution and cellular plasticity in hepatoblastoma
Hepatoblastoma (HB) is the most frequent paediatric liver tumour with heterogeneous cellular phenotypes that influence clinical outcomes. Here, the authors integrate bulk, single-cell, and spatial multi-omics to characterise HB cells, and find that clonal evolution and epigenetic plasticity shape response to therapy.
- Amélie Roehrig
- , Theo Z. Hirsch
- & Eric Letouzé
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Article
| Open AccessThe evolutionary impact of childhood cancer on the human gene pool
Pathogenic germline variants associated with childhood cancer risk could be subject to evolutionary constraints. Here, the authors analyse publicly available germline data in large cohorts and observe that paediatric cancer predisposition syndrome genes are highly constrained in the general population.
- Ulrik Kristoffer Stoltze
- , Jon Foss-Skiftesvik
- & Kjeld Schmiegelow
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Article
| Open AccessASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97
VCP/p97 is identified as a co-factor to the fusion oncoprotein ASPSCR1::TFE3. They co-localize on chromatin, co-dependent for enhancer looping and transcriptional regulation in alveolar soft part sarcomas and Xp11- rearranged renal cell carcinomas.
- Amir Pozner
- , Li Li
- & Kevin B. Jones
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Article
| Open AccessPhosphorylation of human glioma-associated oncogene 1 on Ser937 regulates Sonic Hedgehog signaling in medulloblastoma
Upregulation of GLI1 of has previously been reported in sonic hedgehog (SHH) driven medulloblastoma and basal cell carcinoma (BCC). Here, the authors find that SHH-inactivation of p38 results in stabilization of the transcription factor GLI1 via dephosphorylation at Ser937, resulting in expression of SHH genes and presenting a potential therapy strategy for medulloblastoma and BCC.
- Ling-Hui Zeng
- , Chao Tang
- & Jirong Wang
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Article
| Open AccessTFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex
Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and tumors in multiple organs. Here, the authors show that TFEB is the primary driver of renal disease and mTORC1 hyperactivation in TSC.
- Nicola Alesi
- , Damir Khabibullin
- & Elizabeth P. Henske
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Article
| Open AccessDevelopmental basis of SHH medulloblastoma heterogeneity
The role of developmental pathways in medulloblastoma tumours (MB) with sonic hedgehog (SHH) activation remains to be explored. Here, the authors perform multi-omic analysis and characterise the key transcriptomic and metabolic patterns of highly differentiated cells in SHH MBs.
- Maxwell P. Gold
- , Winnie Ong
- & Ernest Fraenkel
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Article
| Open AccessCompartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage
The mechanisms regulating the balance between proliferation and differentiation in medulloblastomas with extensive nodularity (MBEN) remain poorly understood. Here, single cell multi-omics and spatial analysis characterises the spatial tissue organisation of MBEN in the context of the developmental trajectory.
- David R. Ghasemi
- , Konstantin Okonechnikov
- & Kristian W. Pajtler
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Article
| Open AccessGenetic and epigenetic features of bilateral Wilms tumor predisposition in patients from the Children’s Oncology Group AREN18B5-Q
The genetic and epigenetic predisposition of bilateral Wilms tumour remains to be investigated. Here, the authors perform multiomics analysis and identify the predominant genetic and epigenetic events associated with bilateral Wilms tumour predisposition.
- Andrew J. Murphy
- , Changde Cheng
- & Xiang Chen
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Article
| Open AccessMYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting
SKP2 is an oncogenic E3-ubiquitin ligase. Here the authors show that SKP2 is epigenetically regulated by the muscle lineage transcription factor MYOD, supports tumorigenesis in the Fusion Negative (FN) subtype of rhabdomyosarcoma (RMS) and impairs differentiation promoting degradation of p57Kip2.
- Silvia Pomella
- , Matteo Cassandri
- & Rossella Rota
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Article
| Open AccessMosaic chromosomal alterations in peripheral blood leukocytes of children in sub-Saharan Africa
Mosaic chromosomal alterations (mCAs) in peripheral blood leukocytes are associated with an increased risk of malignancy. Here, the authors use genome-wide genotyping array data to investigate the prevalence of mCAs in sub-Saharan African children with versus those without Burkitt lymphoma.
- Weiyin Zhou
- , Anja Fischer
- & Sam M. Mbulaiteye
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Article
| Open AccessDelineating the interplay between oncogenic pathways and immunity in anaplastic Wilms tumors
Treatment of diffuse anaplastic Wilms tumours (DAWT) remains a challenge. Here, the authors perform multi-omic analysis and identify a desert-like DAWT subtype accounting for one third of DAWT cases and suggest treating them with HDAC and/or WEE1 inhibitors.
- Xiaoping Su
- , Xiaofan Lu
- & Gabriel G. Malouf
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Article
| Open AccessGenomic profiling of subcutaneous patient-derived xenografts reveals immune constraints on tumor evolution in childhood solid cancer
Subcutaneous patient-derived xenografts are a common tool in cancer research. Here, the authors compare 65 paired early passage xenografts to their original paediatric tumour and show clonal evolution determines seeding of the xenograft.
- Funan He
- , Abhik M. Bandyopadhyay
- & Siyuan Zheng
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Article
| Open AccessTargetable lesions and proteomes predict therapy sensitivity through disease evolution in pediatric acute lymphoblastic leukemia
The role of clonal evolution on the actionable proteome and response to therapy in childhood acute lymphoblastic leukemia (ALL) remains unknown. Here, targeted sequencing and proteomic analysis of paired ALL diagnosis and relapsed samples revealed PARP1 as a potential therapeutic target.
- Amanda C. Lorentzian
- , Jenna Rever
- & Philipp F. Lange
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Article
| Open AccessPAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors
Histologically, PAX3-FOXO1 (P3F) fusion-positive rhabdomyosarcoma (FP-RMS) resembles muscles cells, however, its cell-of-origin is less clear. Here, the authors demonstrate that P3F expression induces endothelial cells reprogramming into functional myogenic stem cells, driving the formation of FP-RMS in mouse models.
- Madeline B. Searcy
- , Randolph K. Larsen IV
- & Mark E. Hatley
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Article
| Open AccessA CRISPR-drug perturbational map for identifying compounds to combine with commonly used chemotherapeutics
Combining chemotherapeutics can be beneficial but identifying effective combinations from the vast array of possibilities is resource and time consuming. Here, the authors perform a high-throughput targeted CRISPR knock-out screen identify druggable gene targets which alter sensitivity to chemotherapies. In doing so, they identify DNA-PK inhibition as a sensitiser of neuroblastomas to doxorubicin.
- Hyeong-Min Lee
- , William C. Wright
- & Paul Geeleher
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Article
| Open AccessPreneoplastic liver colonization by 11p15.5 altered mosaic cells in young children with hepatoblastoma
Paediatric liver cancer is rare, and often associated with a predisposition syndrome. Here, the authors show that 11p15.5 mosaic alteration in the liver is a pre-neoplastic lesion associated with hepatoblastoma, and spatial transcriptomics together with single-nucleus RNAseq identify a an altered zonation in the liver of these patients.
- Jill Pilet
- , Theo Z. Hirsch
- & Jessica Zucman-Rossi
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Article
| Open AccessSingle-cell analysis reveals altered tumor microenvironments of relapse- and remission-associated pediatric acute myeloid leukemia
Single-cell RNA-seq could help identify acute myeloid leukaemia (AML) patients at high risk of relapse after therapy. Here, the authors use single-cell RNA-seq from paediatric AML samples to construct a 7-gene signature that can identify malignant cells at diagnosis, which are distinctly associated with relapse or complete remission.
- Hope Mumme
- , Beena E. Thomas
- & Manoj Bhasin
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Article
| Open AccessMLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia
Previous studies have reported MLL-AF4 binding at intragenic and intergenic enhancers, however, the role of MLL-AF4 in enhancer function remains to be investigated. Here, the authors show that MLL-AF4 cooperates with PAF1 and FACT at enhancers to promote high-density interactions with oncogene promoters in leukemia.
- Nicholas T. Crump
- , Alastair L. Smith
- & Thomas A. Milne
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Article
| Open AccessMAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas
The MAPK pathway is a key driver of pediatric low-grade gliomas (pLGG); however, response to MAPK inhibitors (MAPKi) in pLGG patients is not consistent. Here, the authors develop MAPKi sensitivity scores (MSS) to predict response to MAPKi and apply them to bulk and single-cell sequencing datasets from pLGG patients and preclinical models.
- Romain Sigaud
- , Thomas K. Albert
- & Till Milde
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Article
| Open AccessSIX1 and EWS/FLI1 co-regulate an anti-metastatic gene network in Ewing Sarcoma
The tumour-specific functions of SIX1 homeoprotein in Ewing sarcoma (ES) remain poorly understood. Here, the authors suggest that SIX1, which enhances metastasis in most tumour types, suppresses ES metastasis by co-regulating EWS/FLI1 target genes.
- Connor J. Hughes
- , Kaiah M. Fields
- & Heide L. Ford
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Article
| Open AccessGenome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma
The availability of relevant animal models that can recapitulate high-risk hepatoblastoma will help to better understand its pathogenesis. Here the authors report and characterize a hepatocyte-specific, MYC-driven hepatoblastoma mouse model and show it recapitulates the human hepatoblastoma pathophysiology.
- Jie Fang
- , Shivendra Singh
- & Jun Yang
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Article
| Open AccessDefining the landscape of circular RNAs in neuroblastoma unveils a global suppressive function of MYCN
The role of circular RNAs (circRNAs) in modulating gene expression in cancer remains to be investigated. Here, the authors perform whole transcriptome sequencing in 104 primary neuroblastomas and reveal the involvement of MYCN in regulating circRNAs.
- Steffen Fuchs
- , Clara Danßmann
- & Johannes H. Schulte
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Article
| Open AccessSingle-cell transcriptomics reveals immune suppression and cell states predictive of patient outcomes in rhabdomyosarcoma
The cellular differentiation states of paediatric rhabdomyosarcoma (RMS) remain to be explored. Here, single-cell RNA sequencing analysis of RMS tumours reveals an immunosuppressive microenvironment and distinct transcriptional programs predictive of patient outcomes.
- Jeff DeMartino
- , Michael T. Meister
- & Jarno Drost
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Article
| Open AccessIntegrated genomic analysis reveals aberrations in WNT signaling in germ cell tumors of childhood and adolescence
Genomic landscape studies of malignant germ cell tumors (GCTs) that occur in children, adolescents and young adults are limited. Here the authors perform multi-omics profiling of different types of GCTs across the age spectrum from 0–24 years and show that WNT signalling pathway is activated in GCTs and is associated with poor clinical outcomes.
- Lin Xu
- , Joshua L. Pierce
- & James F. Amatruda
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Article
| Open AccessCirculating tumor DNA reveals mechanisms of lorlatinib resistance in patients with relapsed/refractory ALK-driven neuroblastoma
Inhibition of ALK is initially effective in patients with ALK-driven lung cancer but resistance often arises. Here, the authors use circulating tumour DNA, collected as part of a phase I trial investigating lorlatinib (ALK inhibitor) in pediatric patients with ALK-driven neuroblastoma, to detect early resistance mechanisms.
- Esther R. Berko
- , Gabriela M. Witek
- & Yaël P. Mossé
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Article
| Open AccessReversible transitions between noradrenergic and mesenchymal tumor identities define cell plasticity in neuroblastoma
Noradrenergic and mesenchymal cell states have been proposed in neuroblastoma, but their contributions to the tumour are not clearly understood. Here, the authors used in vitro and in vivo models, as well as single-cell RNA-seq, to characterise noradrenergic and mesenchymal cells and their phenotypic plasticity in neuroblastoma.
- Cécile Thirant
- , Agathe Peltier
- & Isabelle Janoueix-Lerosey
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Article
| Open AccessOrganoid models of fibrolamellar carcinoma mutations reveal hepatocyte transdifferentiation through cooperative BAP1 and PRKAR2A loss
An in-depth understanding of the molecular pathogenesis of fibrolamellar carcinoma (FLC) is hampered due to limited human preclinical models. Here the authors engineer human organoids to reflect different FLC genetic backgrounds and show that hepatocytes can be a cell-of-origin of FLC that transdifferentiate into ductal/progenitor like cells due to combined BAP1 and PRKAR2A loss.
- Laura Rüland
- , Francesco Andreatta
- & Benedetta Artegiani
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Article
| Open AccessMetabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma
The molecular mechanisms underlying MYC overexpression in group 3 medulloblastoma remain to be explored. Here, the authors highlight the involvement of the mitochondrial pyruvate carrier- SOD2 signalling pathway in the regulation of MYC protein abundance.
- Emma Martell
- , Helgi Kuzmychova
- & Tanveer Sharif
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Article
| Open AccessThe m6A reader YTHDC1 and the RNA helicase DDX5 control the production of rhabdomyosarcoma-enriched circRNAs
Rhabdomyosarcoma (RMS) is the most diffused soft tissue sarcoma in children and adolescents. Herein, the authors identify the m6A machinery and the RNA helicase DDX5 as factors responsible for the increase of a subset of circRNAs in RMS, providing protein and RNA candidates for the study of its tumorigenicity.
- Dario Dattilo
- , Gaia Di Timoteo
- & Irene Bozzoni
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Article
| Open AccessEtiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication
Oncogenic gene fusions are frequent in childhood cancers but remain poorly understood and untargeted. Here, the authors identify 272 oncogenic fusions in transcriptomics data from 5190 childhood cancer patients, revealing their possible etiologies, their links with tumor progression and evolution, and their potential as therapeutic targets.
- Yanling Liu
- , Jonathon Klein
- & Xiaotu Ma
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Article
| Open AccessClonal origin and development of high hyperdiploidy in childhood acute lymphoblastic leukaemia
High hyperdiploid acute lymphoblastic leukaemia (HeH ALL) is driven by nonrandom chromosomal gains, which have been suggested to arise early - even before birth. Here, the authors use single-cell whole genome sequencing and in silico modelling to show that HeH ALL aneuploidies could originate early and follow punctuated evolution.
- Eleanor L. Woodward
- , Minjun Yang
- & Kajsa Paulsson
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Article
| Open AccessSOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry
The development of neuroblastoma (NB) is regulated by multiple core transcription factors. Here, SOX11 is identified as a potential epigenetic master regulator upstream of the core regulatory circuitry in adrenergic high-risk neuroblastoma.
- Bieke Decaesteker
- , Amber Louwagie
- & Frank Speleman
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Article
| Open AccessARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors
CDKN2A loss and p53 mutations are rare in MYC-driven Group 3 medulloblastomas (MBs). Here the authors generated a transgenic mouse model of Group 3 MB by MYC overexpression and show that MYC suppresses ARF to drive tumorigenesis.
- Oliver J. Mainwaring
- , Holger Weishaupt
- & Fredrik J. Swartling
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Article
| Open AccessProteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia
KMT2A rearranged infant acute lymphoblastic leukemia patients have a poor prognosis. Here, the authors use high throughput drug screening on primary infant specimens to identify a clinically active chemotherapy combination.
- Jennifer L. Kamens
- , Stephanie Nance
- & Tanja A. Gruber
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Article
| Open AccessGermline TP53 mutations undergo copy number gain years prior to tumor diagnosis
Li-Fraumeni syndrome (LFS) is associated with pathogenic germline TP53 variants and predisposes patients to cancer; understanding the evolution and drivers of LFS-related tumours remains crucial. Here, the authors analyse 22 LFS tumours using whole-genome sequencing and reconstruct the evolution and timing of somatic driver alterations.
- Nicholas Light
- , Mehdi Layeghifard
- & Adam Shlien
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Article
| Open AccessCharacterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma
MYC amplification is an independent prognostic factor for the most aggressive subgroup (Group 3) of pediatric medulloblastoma (G3 MB). Here, the authors highlight the role of the RNA-binding protein, Musashi-1 (MSI1) in G3 MB and identify MSI1-bound targets sharing MYC associated pathways.
- Michelle M. Kameda-Smith
- , Helen Zhu
- & Sheila K. Singh
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Article
| Open AccessEpigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas
While recurrence is frequent in ependymoma, the underlying molecular mechanisms remain to be explored. Here, the authors investigate epigenetic, genetic and tumorigenic changes in 30 patient-matched repeated relapses over 13 years and identify distinct patterns of DNA methylation.
- Sibo Zhao
- , Jia Li
- & Xiao-Nan Li
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Article
| Open AccessCharacterizing DNA methylation signatures of retinoblastoma using aqueous humor liquid biopsy
Retinoblastoma response to treatment is difficult to predict. Here, the authors show that DNA methylation of cfDNA from aqueous humour is altered in retinoblastoma patients and can be used to identify the molecular subtypes and potentially predict treatment response.
- Hong-Tao Li
- , Liya Xu
- & Jesse L. Berry
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Article
| Open AccessMulti-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia
The molecular heterogeneity of KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) remains poorly characterised. Here, the authors perform multi-omics analysis for 84 ALL patients and suggest 5 distinct subgroups for risk stratification and personalised treatment.’
- Tomoya Isobe
- , Masatoshi Takagi
- & Junko Takita
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Article
| Open AccessSingle-cell analysis of hepatoblastoma identifies tumor signatures that predict chemotherapy susceptibility using patient-specific tumor spheroids
The mechanisms of tumor heterogeneity in pediatric hepatoblastoma remain poorly characterized. Here, the authors perform single cell RNA sequencing and identify 5 signatures with distinct responses to chemotherapy using patient-derived hepatoblastoma spheroid cultures.
- Hanbing Song
- , Simon Bucher
- & Bruce Wang