Diversité et plasticité des tumeurs de l’enfant

Publications de l’équipe

Année de publication : 2021

Leandro M Colli, Lea Jessop, Timothy A Myers, Sabrina Y Camp, Mitchell J Machiela, Jiyeon Choi, Renato Cunha, Olusegun Onabajo, Grace C Mills, Virginia Schmid, Seth A Brodie, Olivier Delattre, David R Mole, Mark P Purdue, Kai Yu, Kevin M Brown, Stephen J Chanock (2021 Aug 14)

Altered regulation of DPF3, a member of the SWI/SNF complexes, underlies the 14q24 renal cancer susceptibility locus.

American journal of human genetics : 1590-1610 : DOI : S0002-9297(21)00277-9 En savoir plus
Résumé

Our study investigated the underlying mechanism for the 14q24 renal cell carcinoma (RCC) susceptibility risk locus identified by a genome-wide association study (GWAS). The sentinel single-nucleotide polymorphism (SNP), rs4903064, at 14q24 confers an allele-specific effect on expression of the double PHD fingers 3 (DPF3) of the BAF SWI/SNF complex as assessed by massively parallel reporter assay, confirmatory luciferase assays, and eQTL analyses. Overexpression of DPF3 in renal cell lines increases growth rates and alters chromatin accessibility and gene expression, leading to inhibition of apoptosis and activation of oncogenic pathways. siRNA interference of multiple DPF3-deregulated genes reduces growth. Our results indicate that germline variation in DPF3, a component of the BAF complex, part of the SWI/SNF complexes, can lead to reduced apoptosis and activation of the STAT3 pathway, both critical in RCC carcinogenesis. In addition, we show that altered DPF3 expression in the 14q24 RCC locus could influence the effectiveness of immunotherapy treatment for RCC by regulating tumor cytokine secretion and immune cell activation.

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Anna Sole, Sandrine Grossetête, Maxime Heintzé, Loelia Babin, Sakina Zaïdi, Patrick Revy, Benjamin Renouf, Anne De Cian, Carine Giovannangeli, Cécile Pierre-Eugène, Isabelle Janoueix-Lerosey, Lucile Couronné, Sophie Kaltenbach, Mark Tomishima, Maria Jasin, Thomas G P Grünewald, Olivier Delattre, Didier Surdez, Erika Brunet (2021 Aug 3)

Unraveling Ewing Sarcoma Tumorigenesis Originating from Patient-Derived Mesenchymal Stem Cells.

Cancer research : 4994-5006 : DOI : 10.1158/0008-5472.CAN-20-3837 En savoir plus
Résumé

Ewing sarcoma is characterized by pathognomonic translocations, most frequently fusing with . An estimated 30% of Ewing sarcoma tumors also display genetic alterations in , , or (). Numerous attempts to develop relevant Ewing sarcoma models from primary human cells have been unsuccessful in faithfully recapitulating the phenotypic, transcriptomic, and epigenetic features of Ewing sarcoma. In this study, by engineering the t(11;22)(q24;q12) translocation together with a combination of SPC mutations, we generated a wide collection of immortalized cells (EWIma cells) tolerating EWSR1-FLI1 expression from primary mesenchymal stem cells (MSC) derived from a patient with Ewing sarcoma. Within this model, alterations strongly favored Ewing sarcoma oncogenicity. Xenograft experiments with independent EWIma cells induced tumors and metastases in mice, which displayed features of Ewing sarcoma. EWIma cells presented balanced but also more complex translocation profiles mimicking chromoplexy, which is frequently observed in Ewing sarcoma and other cancers. Collectively, these results demonstrate that bone marrow-derived MSCs are a source of origin for Ewing sarcoma and also provide original experimental models to investigate Ewing sarcomagenesis. SIGNIFICANCE: These findings demonstrate that Ewing sarcoma can originate from human bone-marrow-derived mesenchymal stem cells and that recurrent mutations support EWSR1-FLI1 translocation-mediated transformation.

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Julien Vibert, Gaëlle Pierron, Camille Benoist, Nadège Gruel, Delphine Guillemot, Anne Vincent-Salomon, Christophe Le Tourneau, Alain Livartowski, Odette Mariani, Sylvain Baulande, François-Clément Bidard, Olivier Delattre, Joshua J Waterfall, Sarah Watson (2021 Jul 29)

Identification of Tissue of Origin and Guided Therapeutic Applications in Cancers of Unknown Primary Using Deep Learning and RNA Sequencing (TransCUPtomics).

The Journal of molecular diagnostics : JMD : 1380-1392 : DOI : S1525-1578(21)00215-4 En savoir plus
Résumé

Cancers of unknown primary (CUP) are metastatic cancers for which the primary tumor is not found despite thorough diagnostic investigations. Multiple molecular assays have been proposed to identify the tissue of origin (TOO) and inform clinical care; however, none has been able to combine accuracy, interpretability, and easy access for routine use. We developed a classifier tool based on the training of a variational autoencoder to predict tissue of origin based on RNA-sequencing data. We used as training data 20,918 samples corresponding to 94 different categories, including 39 cancer types and 55 normal tissues. The TransCUPtomics classifier was applied to a retrospective cohort of 37 CUP patients and 11 prospective patients. TransCUPtomics exhibited an overall accuracy of 96% on reference data for TOO prediction. The TOO could be identified in 38 (79%) of 48 CUP patients. Eight of 11 prospective CUP patients (73%) could receive first-line therapy guided by TransCUPtomics prediction, with responses observed in most patients. The variational autoencoder added further utility by enabling prediction interpretability, and diagnostic predictions could be matched to detection of gene fusions and expressed variants. TransCUPtomics confidently predicted TOO for CUP and enabled tailored treatments leading to significant clinical responses. The interpretability of our approach is a powerful addition to improve the management of CUP patients.

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Irene Jiménez, Éléonore Frouin, Mathieu Chicard, Catherine Dehainault, Jessica Le Gall, Camille Benoist, Arnaud Gauthier, Eve Lapouble, Claude Houdayer, François Radvanyi, Virginie Bernard, Hervé J Brisse, Marion Gauthier-Villars, Dominique Stoppa-Lyonnet, Sylvain Baulande, Nathalie Cassoux, Livia Lumbroso, Alexandre Matet, Isabelle Aerts, Victor Renault, François Doz, Lisa Golmard, Olivier Delattre, Gudrun Schleiermacher (2021 Jul 23)

Molecular diagnosis of retinoblastoma by circulating tumor DNA analysis.

European journal of cancer (Oxford, England : 1990) : 277-287 : DOI : S0959-8049(21)00373-7 En savoir plus
Résumé

The analysis of circulating tumor DNA (ctDNA), a fraction of total cell-free DNA (cfDNA), might be of special interest in retinoblastoma patients. Because the accessibility to tumor tissue is very limited in these patients, either for histopathological diagnosis of suspicious intraocular masses (biopsies are proscribed) or for somatic RB1 studies and genetic counseling (due to current successful conservative approaches), we aim to validate the detection of ctDNA in plasma of non-hereditary retinoblastoma patients by molecular analysis of RB1 gene.

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Angela Bellini, Ulrike Pötschger, Virginie Bernard, Eve Lapouble, Sylvain Baulande, Peter F Ambros, Nathalie Auger, Klaus Beiske, Marie Bernkopf, David R Betts, Jaydutt Bhalshankar, Nick Bown, Katleen de Preter, Nathalie Clément, Valérie Combaret, Jaime Font de Mora, Sally L George, Irene Jiménez, Marta Jeison, Barbara Marques, Tommy Martinsson, Katia Mazzocco, Martina Morini, Annick Mühlethaler-Mottet, Rosa Noguera, Gaelle Pierron, Maria Rossing, Sabine Taschner-Mandl, Nadine Van Roy, Ales Vicha, Louis Chesler, Walentyna Balwierz, Victoria Castel, Martin Elliott, Per Kogner, Geneviève Laureys, Roberto Luksch, Josef Malis, Maja Popovic-Beck, Shifra Ash, Olivier Delattre, Dominique Valteau-Couanet, Deborah A Tweddle, Ruth Ladenstein, Gudrun Schleiermacher (2021 Jun 11)

Frequency and Prognostic Impact of Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1).

Journal of clinical oncology : official journal of the American Society of Clinical Oncology : JCO2100086 : DOI : 10.1200/JCO.21.00086 En savoir plus
Résumé

In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact.

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GAUTIER Margot, THIRIANTCécile, DELATTRE Olivier, JANOUEIX-LEROSEY Isabelle (2021 Jun 10)

Plasticity in Neuroblastoma Cell Identity Defines a Noradrenergic-to-Mesenchymal Transition (NMT)

Cancers (Basel) : 13(12):2904. : DOI : 10.3390/cancers13122904 En savoir plus
Résumé

Neuroblastoma, a pediatric cancer of the peripheral sympathetic nervous system, is characterized by an important clinical heterogeneity, and high-risk tumors are associated with a poor overall survival. Neuroblastoma cells may present with diverse morphological and biochemical properties in vitro, and seminal observations suggested that interconversion between two phenotypes called N-type and S-type may occur. In 2017, two main studies provided novel insights into these subtypes through the characterization of the transcriptomic and epigenetic landscapes of a panel of neuroblastoma cell lines. In this review, we focus on the available data that define neuroblastoma cell identity and propose to use the term noradrenergic (NOR) and mesenchymal (MES) to refer to these identities. We also address the question of transdifferentiation between both states and suggest that the plasticity between the NOR identity and the MES identity defines a noradrenergic-to-mesenchymal transition, reminiscent of but different from the well-established epithelial-to-mesenchymal transition.

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Peter Peneder, Adrian M Stütz, Didier Surdez, Manuela Krumbholz, Sabine Semper, Mathieu Chicard, Nathan C Sheffield, Gaelle Pierron, Eve Lapouble, Marcus Tötzl, Bekir Ergüner, Daniele Barreca, André F Rendeiro, Abbas Agaimy, Heidrun Boztug, Gernot Engstler, Michael Dworzak, Marie Bernkopf, Sabine Taschner-Mandl, Inge M Ambros, Ola Myklebost, Perrine Marec-Bérard, Susan Ann Burchill, Bernadette Brennan, Sandra J Strauss, Jeremy Whelan, Gudrun Schleiermacher, Christiane Schaefer, Uta Dirksen, Caroline Hutter, Kjetil Boye, Peter F Ambros, Olivier Delattre, Markus Metzler, Christoph Bock, Eleni M Tomazou (2021 May 29)

Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden.

Nature communications : 3230 : DOI : 10.1038/s41467-021-23445-w En savoir plus
Résumé

Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. Moreover, we benchmark different metrics for cell-free DNA fragmentation analysis, and we introduce the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. Finally, we combine several fragmentation-based metrics into an integrated machine learning classifier for liquid biopsy analysis that exploits widespread epigenetic deregulation and is tailored to cancers with low mutation rates. Clinical associations highlight the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent genetic aberrations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers.

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Hai-Feng Zhang, Christopher S Hughes, Wei Li, Jian-Zhong He, Didier Surdez, Amal M El-Naggar, Hongwei Cheng, Anna Prudova, Alberto Delaidelli, Gian Luca Negri, Xiaojun Li, Maj Sofie Orum-Madsen, Michael M Lizardo, Htoo Zarni Oo, Shane Colborne, Taras Shyp, Renata Scopim-Ribeiro, Colin A Hammond, Anne-Chloe Dhez, Sofya Langman, Jonathan Km Lim, Sonia Hy Kung, Amy Li, Anne Steino, Mads Daugaard, Seth J Parker, Ramon I Klein Geltink, Rimas J Orentas, Li-Yan Xu, Gregg B Morin, Olivier Delattre, Dimiter S Dimitrov, Poul H Sorensen (2021 May 22)

Proteomic screens for suppressors of anoikis identify IL1RAP as a promising surface target in Ewing sarcoma.

Cancer discovery : DOI : candisc.1690.2020 En savoir plus
Résumé

Cancer cells must overcome anoikis (detachment-induced death) to successfully metastasize. Using proteomic screens, we found that distinct oncoproteins upregulate IL-1 receptor accessory protein (IL1RAP) to suppress anoikis. IL1RAP is directly induced by oncogenic fusions of Ewing sarcoma (EwS), a highly metastatic childhood sarcoma. IL1RAP inactivation triggers anoikis and impedes metastatic dissemination of EwS cells. Mechanistically, IL1RAP binds the cell surface system Xc- transporter to enhance exogenous cystine uptake, thereby replenishing cysteine and the glutathione antioxidant. Under cystine depletion, IL1RAP induces cystathionine gamma lyase (CTH) to activate the transsulfuration pathway for de novo cysteine synthesis. Therefore IL1RAP maintains cyst(e)ine and glutathione pools which are vital for redox homeostasis and anoikis resistance. IL1RAP is minimally expressed in pediatric and adult normal tissues, and human anti-IL1RAP antibodies induce potent antibody-dependent cellular cytotoxicity of EwS cells. Therefore, we define IL1RAP as a new cell surface target in EwS, which is potentially exploitable for immunotherapy.

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Olivier Saulnier, Katia Guedri-Idjouadiene, Marie-Ming Aynaud, Alina Chakraborty, Jonathan Bruyr, Joséphine Pineau, Tina O'Grady, Olivier Mirabeau, Sandrine Grossetête, Bartimée Galvan, Margaux Claes, Zahra Al Oula Hassoun, Benjamin Sadacca, Karine Laud, Sakina Zaïdi, Didier Surdez, Sylvain Baulande, Xavier Rambout, Franck Tirode, Martin Dutertre, Olivier Delattre, Franck Dequiedt (2021 May 19)

ERG transcription factors have a splicing regulatory function involving RBFOX2 that is altered in the EWS-FLI1 oncogenic fusion.

Nucleic acids research : DOI : 10.1093/nar/gkab305 En savoir plus
Résumé

ERG family proteins (ERG, FLI1 and FEV) are a subfamily of ETS transcription factors with key roles in physiology and development. In Ewing sarcoma, the oncogenic fusion protein EWS-FLI1 regulates both transcription and alternative splicing of pre-messenger RNAs. However, whether wild-type ERG family proteins might regulate splicing is unknown. Here, we show that wild-type ERG proteins associate with spliceosomal components, are found on nascent RNAs, and induce alternative splicing when recruited onto a reporter minigene. Transcriptomic analysis revealed that ERG and FLI1 regulate large numbers of alternative spliced exons (ASEs) enriched with RBFOX2 motifs and co-regulated by this splicing factor. ERG and FLI1 are associated with RBFOX2 via their conserved carboxy-terminal domain, which is present in EWS-FLI1. Accordingly, EWS-FLI1 is also associated with RBFOX2 and regulates ASEs enriched in RBFOX2 motifs. However, in contrast to wild-type ERG and FLI1, EWS-FLI1 often antagonizes RBFOX2 effects on exon inclusion. In particular, EWS-FLI1 reduces RBFOX2 binding to the ADD3 pre-mRNA, thus increasing its long isoform, which represses the mesenchymal phenotype of Ewing sarcoma cells. Our findings reveal a RBFOX2-mediated splicing regulatory function of wild-type ERG family proteins, that is altered in EWS-FLI1 and contributes to the Ewing sarcoma cell phenotype.

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Mamy Andrianteranagna, Joanna Cyrta, Julien Masliah-Planchon, Karolina Nemes, Alice Corsia, Amaury Leruste, Dörthe Holdhof, Uwe Kordes, Daniel Orbach, Nadège Corradini, Natacha Entz-Werle, Gaëlle Pierron, Marie-Pierre Castex, Anne Brouchet, Noëlle Weingertner, Dominique Ranchère, Paul Fréneaux, Olivier Delattre, Jonathan Bush, Alexandra Leary, Michael C Frühwald, Ulrich Schüller, Nicolas Servant, Franck Bourdeaut (2021 May 17)

SMARCA4-deficient rhabdoid tumours show intermediate molecular features between SMARCB1-deficient rhabdoid tumours and small cell carcinomas of the ovary, hypercalcaemic type.

The Journal of pathology : DOI : 10.1002/path.5705 En savoir plus
Résumé

Extracranial rhabdoid tumours (ECRT) are an aggressive malignancy of infancy and early childhood. The vast majority of cases demonstrate inactivation of SMARCB1 (ECRT ) on a background of a remarkably stable genome, a low mutational burden, and no other recurrent mutations. Rarely, ECRT can harbour the alternative inactivation of SMARCA4 (ECRT ) instead of SMARCB1. However, very few ECRT cases have been published to date, and a systematic characterization of ECRT is missing from the literature. In this study, we report the clinical, pathological, and genomic features of additional cases of ECRT , and show that they are comparable to those of ECRT We also assess whether ECRT , ECRT and small cell carcinomas of the ovary, hypercalcaemic type (SCCOHT) represent distinct or overlapping entities at a molecular level. Using DNA methylation and transcriptomics-based tumour classification approaches, we demonstrate that ECRT display molecular features intermediate between SCCOHT and ECRT ; however, ECRT appear to be more closely related to SCCOHT by DNA methylation. Conversely, both transcriptomics and DNA methylation show a larger gap between SCCOHT and ECRT , potentially supporting their continuous separate classification. Lastly, we show that ECRT display concomitant lack of SMARCA4 (BRG1) and SMARCA2 (BRM) expression at the protein level, similar to what is seen in SCCOHT. Overall, our results expand the knowledge on this rare tumour type and explore the similarities and differences among entities from the ‘rhabdoid tumour’ spectrum. This article is protected by copyright. All rights reserved.

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Didier Surdez, Sakina Zaidi, Sandrine Grossetête, Karine Laud-Duval, Anna Sole Ferre, Lieke Mous, Thomas Vourc'h, Franck Tirode, Gaelle Pierron, Virginie Raynal, Sylvain Baulande, Erika Brunet, Véronique Hill, Olivier Delattre (2021 Apr 30)

STAG2 mutations alter CTCF-anchored loop extrusion, reduce cis-regulatory interactions and EWSR1-FLI1 activity in Ewing sarcoma.

Cancer cell : DOI : 10.1016/j.ccell.2021.04.001 En savoir plus
Résumé

STAG2, a cohesin family gene, is among the most recurrently mutated genes in cancer. STAG2 loss of function (LOF) is associated with aggressive behavior in Ewing sarcoma, a childhood cancer driven by aberrant transcription induced by the EWSR1-FLI1 fusion oncogene. Here, using isogenic Ewing cells, we show that, while STAG2 LOF profoundly changes the transcriptome, it does not significantly impact EWSR1-FLI1, CTCF/cohesin, or acetylated H3K27 DNA binding patterns. In contrast, it strongly alters the anchored dynamic loop extrusion process at boundary CTCF sites and dramatically decreases promoter-enhancer interactions, particularly affecting the expression of genes regulated by EWSR1-FLI1 at GGAA microsatellite neo-enhancers. Down-modulation of cis-mediated EWSR1-FLI1 activity, observed in STAG2-LOF conditions, is associated with enhanced migration and invasion properties of Ewing cells previously observed in EWSR1-FLI1 cells. Our study illuminates a process whereby STAG2-LOF fine-tunes the activity of an oncogenic transcription factor through altered CTCF-anchored loop extrusion and cis-mediated enhancer mechanisms.

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Année de publication : 2020

Gabriele Manzella, Leonie D Schreck, Willemijn B Breunis, Jan Molenaar, Hans Merks, Frederic G Barr, Wenyue Sun, Michaela Römmele, Luduo Zhang, Joelle Tchinda, Quy A Ngo, Peter Bode, Olivier Delattre, Didier Surdez, Bharat Rekhi, Felix K Niggli, Beat W Schäfer, Marco Wachtel (2020 Sep 16)

Phenotypic profiling with a living biobank of primary rhabdomyosarcoma unravels disease heterogeneity and AKT sensitivity.

Nature communications : 4629 : DOI : 10.1038/s41467-020-18388-7 En savoir plus
Résumé

Cancer therapy is currently shifting from broadly used cytotoxic drugs to patient-specific precision therapies. Druggable driver oncogenes, identified by molecular analyses, are present in only a subset of patients. Functional profiling of primary tumor cells could circumvent these limitations, but suitable platforms are unavailable for most cancer entities. Here, we describe an in vitro drug profiling platform for rhabdomyosarcoma (RMS), using a living biobank composed of twenty RMS patient-derived xenografts (PDX) for high-throughput drug testing. Optimized in vitro conditions preserve phenotypic and molecular characteristics of primary PDX cells and are compatible with propagation of cells directly isolated from patient tumors. Besides a heterogeneous spectrum of responses of largely patient-specific vulnerabilities, profiling with a large drug library reveals a strong sensitivity towards AKT inhibitors in a subgroup of RMS. Overall, our study highlights the feasibility of in vitro drug profiling of primary RMS for patient-specific treatment selection in a co-clinical setting.

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Inge M Ambros, Gian-Paolo Tonini, Ulrike Pötschger, Nicole Gross, Véronique Mosseri, Klaus Beiske, Ana P Berbegall, Jean Bénard, Nick Bown, Huib Caron, Valérie Combaret, Jerome Couturier, Raffaella Defferrari, Olivier Delattre, Marta Jeison, Per Kogner, John Lunec, Barbara Marques, Tommy Martinsson, Katia Mazzocco, Rosa Noguera, Gudrun Schleiermacher, Alexander Valent, Nadine Van Roy, Eva Villamon, Dasa Janousek, Ingrid Pribill, Evgenia Glogova, Edward F Attiyeh, Michael D Hogarty, Tom F Monclair, Keith Holmes, Dominique Valteau-Couanet, Victoria Castel, Deborah A Tweddle, Julie R Park, Sue Cohn, Ruth Ladenstein, Maja Beck-Popovic, Bruno De Bernardi, Jean Michon, Andrew D J Pearson, Peter F Ambros (2020 Sep 9)

Age Dependency of the Prognostic Impact of Tumor Genomics in Localized Resectable -Nonamplified Neuroblastomas. Report From the SIOPEN Biology Group on the LNESG Trials and a COG Validation Group.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology : 3685-3697 : DOI : 10.1200/JCO.18.02132 En savoir plus
Résumé

For localized, resectable neuroblastoma without amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome.

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Shu-Hong Lin, Joshua N Sampson, Thomas G P Grünewald, Didier Surdez, Stephanie Reynaud, Olivier Mirabeau, Eric Karlins, Rebeca Alba Rubio, Sakina Zaidi, Sandrine Grossetête-Lalami, Stelly Ballet, Eve Lapouble, Valérie Laurence, Jean Michon, Gaelle Pierron, Heinrich Kovar, Udo Kontny, Anna González-Neira, Javier Alonso, Ana Patino-Garcia, Nadège Corradini, Perrine Marec Bérard, Jeremy Miller, Neal D Freedman, Nathaniel Rothman, Brian D Carter, Casey L Dagnall, Laurie Burdett, Kristine Jones, Michelle Manning, Kathleen Wyatt, Weiyin Zhou, Meredith Yeager, David G Cox, Robert N Hoover, Javed Khan, Gregory T Armstrong, Wendy M Leisenring, Smita Bhatia, Leslie L Robison, Andreas E Kulozik, Jennifer Kriebel, Thomas Meitinger, Markus Metzler, Manuela Krumbholz, Wolfgang Hartmann, Konstantin Strauch, Thomas Kirchner, Uta Dirksen, Lisa Mirabello, Margaret A Tucker, Franck Tirode, Lindsay M Morton, Stephen J Chanock, Olivier Delattre, Mitchell J Machiela (2020 Sep 4)

Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma.

PloS one : e0237792 : DOI : 10.1371/journal.pone.0237792 En savoir plus
Résumé

Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor.

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Johanna Theruvath, Elena Sotillo, Christopher W Mount, Claus Moritz Graef, Alberto Delaidelli, Sabine Heitzeneder, Louai Labanieh, Shaurya Dhingra, Amaury Leruste, Robbie G Majzner, Peng Xu, Sabine Mueller, Derek W Yecies, Martina A Finetti, Daniel Williamson, Pascal D Johann, Marcel Kool, Stefan Pfister, Martin Hasselblatt, Michael C Frühwald, Olivier Delattre, Didier Surdez, Franck Bourdeaut, Stephanie Puget, Sakina Zaidi, Siddhartha S Mitra, Samuel Cheshier, Poul H Sorensen, Michelle Monje, Crystal L Mackall (2020 Apr 29)

Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors.

Nature medicine : DOI : 10.1038/s41591-020-0821-8 En savoir plus
Résumé

Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. ), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.

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