Diversité et plasticité des tumeurs de l’enfant

Publications de l’équipe

Année de publication : 2017

Sheffield NC, Pierron G, Klughammer J, Datlinger P, Schönegger A, Schuster M, Hadler J, Surdez D, Guillemot D, Lapouble E, Freneaux P, Champigneulle J, Bouvier R, Walder D, Ambros IM, Hutter C, Sorz E, Amaral AT, de Álava E, Schallmoser K, Strunk D, Rinner B, Liegl-Atzwanger B, Huppertz B, Leithner A, de Pinieux G, Terrier P, Laurence V, Michon J, Ladenstein R, Holter W, Windhager R, Dirksen U, Ambros PF, Delattre O, Kovar H, Bock C, Tomazou EM. (2017 Mar 23)

DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma.

Nature Médecine- : DOI : 10.1038/nm.4273 En savoir plus
Résumé

Developmental tumors in children and young adults carry few genetic alterations, yet they have diverse clinical presentation. Focusing on Ewingsarcoma, we sought to establish the prevalence and characteristics of epigenetic heterogeneityin genetically homogeneous cancers. We performed genome-scale DNAmethylationsequencing for a large cohort of Ewingsarcomatumors and analyzed epigenetic heterogeneityon three levels: between cancers, between tumors, and within tumors. We observed consistent DNAhypomethylation at enhancers regulated by the disease-defining EWS-FLI1 fusion protein, thus establishing epigenomic enhancer reprogramming as a ubiquitous and characteristic feature of Ewingsarcoma. DNAmethylationdifferences between tumors identified a continuous diseasespectrumunderlying Ewingsarcoma, which reflected the strength of an EWS-FLI1 regulatory signature and a continuum between mesenchymal and stem cell signatures. There was substantial epigenetic heterogeneitywithin tumors, particularly in patients with metastatic disease. In summary, our study provides a comprehensive assessment of epigenetic heterogeneityin Ewingsarcomaand thereby highlights the importance of considering nongenetic aspects of tumor heterogeneityin the context of cancer biology and personalized medicine.

Replier
, Philip C Haycock, Stephen Burgess, Aayah Nounu, Jie Zheng, George N Okoli, Jack Bowden, Kaitlin Hazel Wade, Nicholas J Timpson, David M Evans, Peter Willeit, Abraham Aviv, Tom R Gaunt, Gibran Hemani, Massimo Mangino, Hayley Patricia Ellis, Kathreena M Kurian, Karen A Pooley, Rosalind A Eeles, Jeffrey E Lee, Shenying Fang, Wei V Chen, Matthew H Law, Lisa M Bowdler, Mark M Iles, Qiong Yang, Bradford B Worrall, Hugh Stephen Markus, Rayjean J Hung, Chris I Amos, Amanda B Spurdle, Deborah J Thompson, Tracy A O'Mara, Brian Wolpin, Laufey Amundadottir, Rachael Stolzenberg-Solomon, Antonia Trichopoulou, N Charlotte Onland-Moret, Eiliv Lund, Eric J Duell, Federico Canzian, Gianluca Severi, Kim Overvad, Marc J Gunter, Rosario Tumino, Ulrika Svenson, Andre van Rij, Annette F Baas, Matthew J Bown, Nilesh J Samani, Femke N G van t'Hof, Gerard Tromp, Gregory T Jones, Helena Kuivaniemi, James R Elmore, Mattias Johansson, James Mckay, Ghislaine Scelo, Robert Carreras-Torres, Valerie Gaborieau, Paul Brennan, Paige M Bracci, Rachel E Neale, Sara H Olson, Steven Gallinger, Donghui Li, Gloria M Petersen, Harvey A Risch, Alison P Klein, Jiali Han, Christian C Abnet, Neal D Freedman, Philip R Taylor, John M Maris, Katja K Aben, Lambertus A Kiemeney, Sita H Vermeulen, John K Wiencke, Kyle M Walsh, Margaret Wrensch, Terri Rice, Clare Turnbull, Kevin Litchfield, Lavinia Paternoster, Marie Standl, Gonçalo R Abecasis, John Paul SanGiovanni, Yong Li, Vladan Mijatovic, Yadav Sapkota, Siew-Kee Low, Krina T Zondervan, Grant W Montgomery, Dale R Nyholt, David A van Heel, Karen Hunt, Dan E Arking, Foram N Ashar, Nona Sotoodehnia, Daniel Woo, Jonathan Rosand, Mary E Comeau, W Mark Brown, Edwin K Silverman, John E Hokanson, Michael H Cho, Jennie Hui, Manuel A Ferreira, Philip J Thompson, Alanna C Morrison, Janine F Felix, Nicholas L Smith, Angela M Christiano, Lynn Petukhova, Regina C Betz, Xing Fan, Xuejun Zhang, Caihong Zhu, Carl D Langefeld, Susan D Thompson, Feijie Wang, Xu Lin, David A Schwartz, Tasha Fingerlin, Jerome I Rotter, Mary Frances Cotch, Richard A Jensen, Matthias Munz, Henrik Dommisch, Arne S Schaefer, Fang Han, Hanna M Ollila, Ryan P Hillary, Omar Albagha, Stuart H Ralston, Chenjie Zeng, Wei Zheng, Xiao-Ou Shu, Andre Reis, Steffen Uebe, Ulrike Hüffmeier, Yoshiya Kawamura, Takeshi Otowa, Tsukasa Sasaki, Martin Lloyd Hibberd, Sonia Davila, Gang Xie, Katherine Siminovitch, Jin-Xin Bei, Yi-Xin Zeng, Asta Försti, Bowang Chen, Stefano Landi, Andre Franke, Annegret Fischer, David Ellinghaus, Carlos Flores, Imre Noth, Shwu-Fan Ma, Jia Nee Foo, Jianjun Liu, Jong-Won Kim, David G Cox, Olivier Delattre, Olivier Mirabeau, Christine F Skibola, Clara S Tang, Merce Garcia-Barcelo, Kai-Ping Chang, Wen-Hui Su, Yu-Sun Chang, Nicholas G Martin, Scott Gordon, Tracey D Wade, Chaeyoung Lee, Michiaki Kubo, Pei-Chieng Cha, Yusuke Nakamura, Daniel Levy, Masayuki Kimura, Shih-Jen Hwang, Steven Hunt, Tim Spector, Nicole Soranzo, Ani W Manichaikul, R Graham Barr, Bratati Kahali, Elizabeth Speliotes, Laura M Yerges-Armstrong, Ching-Yu Cheng, Jost B Jonas, Tien Yin Wong, Isabella Fogh, Kuang Lin, John F Powell, Kenneth Rice, Caroline L Relton, Richard M Martin, George Davey Smith (2017 Feb 28)

Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.

JAMA oncology : DOI : 10.1001/jamaoncol.2016.5945 En savoir plus
Résumé

The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.

Replier
G-A Franzetti, K Laud-Duval, W van der Ent, A Brisac, M Irondelle, S Aubert, U Dirksen, C Bouvier, G de Pinieux, E Snaar-Jagalska, P Chavrier, O Delattre (2017 Jan 31)

Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in Ewing sarcoma cells.

Oncogene : DOI : 10.1038/onc.2016.498 En savoir plus
Résumé

Ewing sarcoma is characterized by the expression of the chimeric EWSR1-FLI1 transcription factor. Proteomic analyses indicate that the decrease of EWSR1-FLI1 expression leads to major changes in effectors of the dynamics of the actin cytoskeleton and the adhesion processes with a shift from cell-to-cell to cell-matrix adhesion. These changes are associated with a dramatic increase of in vivo cell migration and invasion potential. Importantly, EWSR1-FLI1 expression, evaluated by single-cell RT-ddPCR/immunofluorescence analyses, and activity, assessed by expression of EWSR1-FLI1 downstream targets, are heterogeneous in cell lines and in tumours and can fluctuate along time in a fully reversible process between EWSR1-FLI1(high) states, characterized by highly active cell proliferation, and EWSR1-FLI1(low) states where cells have a strong propensity to migrate, invade and metastasize. This new model of phenotypic plasticity proposes that the dynamic fluctuation of the expression level of a dominant oncogene is an intrinsic characteristic of its oncogenic potential.Oncogene advance online publication, 30 January 2017; doi:10.1038/onc.2016.498.

Replier
Nathan C Sheffield, Gaelle Pierron, Johanna Klughammer, Paul Datlinger, Andreas Schönegger, Michael Schuster, Johanna Hadler, Didier Surdez, Delphine Guillemot, Eve Lapouble, Paul Freneaux, Jacqueline Champigneulle, Raymonde Bouvier, Diana Walder, Ingeborg M Ambros, Caroline Hutter, Eva Sorz, Ana T Amaral, Enrique de Álava, Katharina Schallmoser, Dirk Strunk, Beate Rinner, Bernadette Liegl-Atzwanger, Berthold Huppertz, Andreas Leithner, Gonzague de Pinieux, Philippe Terrier, Valérie Laurence, Jean Michon, Ruth Ladenstein, Wolfgang Holter, Reinhard Windhager, Uta Dirksen, Peter F Ambros, Olivier Delattre, Heinrich Kovar, Christoph Bock, Eleni M Tomazou (2017 Jan 31)

DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma.

Nature medicine : DOI : 10.1038/nm.4273 En savoir plus
Résumé

Developmental tumors in children and young adults carry few genetic alterations, yet they have diverse clinical presentation. Focusing on Ewing sarcoma, we sought to establish the prevalence and characteristics of epigenetic heterogeneity in genetically homogeneous cancers. We performed genome-scale DNA methylation sequencing for a large cohort of Ewing sarcoma tumors and analyzed epigenetic heterogeneity on three levels: between cancers, between tumors, and within tumors. We observed consistent DNA hypomethylation at enhancers regulated by the disease-defining EWS-FLI1 fusion protein, thus establishing epigenomic enhancer reprogramming as a ubiquitous and characteristic feature of Ewing sarcoma. DNA methylation differences between tumors identified a continuous disease spectrum underlying Ewing sarcoma, which reflected the strength of an EWS-FLI1 regulatory signature and a continuum between mesenchymal and stem cell signatures. There was substantial epigenetic heterogeneity within tumors, particularly in patients with metastatic disease. In summary, our study provides a comprehensive assessment of epigenetic heterogeneity in Ewing sarcoma and thereby highlights the importance of considering nongenetic aspects of tumor heterogeneity in the context of cancer biology and personalized medicine.

Replier
A Bertrand, C Rondenet, J Masliah-Planchon, P Leblond, A de la Fourchardière, D Pissaloux, K Aït-Raïs, D Lequin, A Jouvet, P Freneaux, H Sevestre, D Ranchere-Vince, A Tauziede-Espariat, C-A Maurage, K Silva, G Pierron, O Delattre, P Varlet, D Frappaz, F Bourdeaut (2017 Jan 6)

Rhabdoid component emerging as a subclonal evolution of paediatric glioneuronal tumours.

Neuropathology and applied neurobiology : DOI : 10.1111/nan.12379 En savoir plus
Résumé

Atypical teratoid/rhabdoid tumors (AT/RT) are high-grade tumors partially composed of rhabdoid cells (1). The 1-year overall survival rate is 41% (2). Rhabdoid cells have large eccentric nuclei, a single prominent nucleolus, and abundant cytoplasm with eosinophilic inclusions. The immunohistochemical profile of these cells frequently includes loss of nuclear BAF47 expression due to loss of the SMARCB1 locus combined with a mutation of the other allele (3). This article is protected by copyright. All rights reserved.

Replier
Gudrun Schleiermacher, Olivier Delattre (2017 Jan 2)

Kids Enter the MATCH.

Journal of the National Cancer Institute : DOI : djw305 En savoir plus
Résumé

Replier

Année de publication : 2016

Edoardo Missiaglia, Chris J Shepherd, Ewa Aladowicz, David Olmos, Joanna Selfe, Gaëlle Pierron, Olivier Delattre, Zoe Walters, Janet Shipley (2016 Dec 17)

MicroRNA and gene co-expression networks characterize biological and clinical behavior of rhabdomyosarcomas.

Cancer letters : DOI : S0304-3835(16)30623-1 En savoir plus
Résumé

Rhabdomyosarcomas (RMS) in children and adolescents are heterogeneous sarcomas broadly defined by skeletal muscle features and the presence/absence of PAX3/7-FOXO1 fusion genes. MicroRNAs are small non-coding RNAs that regulate gene expression in a cell context specific manner. Sequencing analyses of microRNAs in 64 RMS revealed expression patterns separating skeletal muscle, fusion gene positive and negative RMS. Integration with parallel gene expression data assigned biological functions to 12 co-expression networks/modules that reassuringly included myogenic roles strongly correlated with microRNAs known in myogenesis and RMS development. Modules also correlated with clinical outcome and fusion status. Regulation of microRNAs by the fusion protein was demonstrated after PAX3-FOXO1 reduction, exemplified by miR-9-5p. MiR-9-5p levels correlated with poor outcome, even within fusion gene positive RMS, and were higher in metastatic versus non-metastatic disease. MiR-9-5p reduction inhibited RMS cell migration. Our findings reveal microRNAs in a regulatory framework of biological and clinical significance in RMS.

Replier
Thomas Pincez, Nathalie Clément, Eve Lapouble, Gaëlle Pierron, Maud Kamal, Ivan Bieche, Virginie Bernard, Paul Fréneaux, Jean Michon, Daniel Orbach, Isabelle Aerts, Hélène Pacquement, Franck Bourdeaut, Irene Jiménez, Estelle Thébaud, Caroline Oudot, Cécile Vérité, Sophie Taque, Cormac Owens, François Doz, Christophe Le Tourneau, Olivier Delattre, Gudrun Schleiermacher (2016 Nov 30)

Feasibility and clinical integration of molecular profiling for target identification in pediatric solid tumors.

Pediatric blood & cancer : DOI : 10.1002/pbc.26365 En savoir plus
Résumé

The role of tumor molecular profiling in directing targeted therapy utilization remains to be defined for pediatric tumors. We aimed to evaluate the feasibility of a sequencing and molecular biology tumor board (MBB) program, and its clinical impact on children with solid tumors.

Replier
Tao He, Didier Surdez, Juha K Rantala, Saija Haapa-Paananen, Jozef Ban, Maximilian Kauer, Eleni Tomazou, Vidal Fey, Javier Alonso, Heinrich Kovar, Olivier Delattre, Kristiina Iljin (2016 Oct 30)

High-throughput RNAi screen in Ewing sarcoma cells identifies leucine rich repeats and WD repeat domain containing 1 (LRWD1) as a regulator of EWS-FLI1 driven cell viability.

Gene : 137-146 : DOI : S0378-1119(16)30827-7 En savoir plus
Résumé

A translocation leading to the formation of an oncogenic EWS-ETS fusion protein defines Ewing sarcoma. The most frequent gene fusion, present in 85 percent of Ewing sarcomas, is EWS-FLI1. Here, a high-throughput RNA interference screen was performed to identify genes whose function is critical for EWS-FLI1 driven cell viability. In total, 6781 genes were targeted by siRNA molecules and the screen was performed both in presence and absence of doxycycline-inducible expression of the EWS-FLI1 shRNA in A673/TR/shEF Ewing sarcoma cells. The Leucine rich repeats and WD repeat Domain containing 1 (LRWD1) targeting siRNA pool was the strongest hit reducing cell viability only in EWS-FLI1 expressing Ewing sarcoma cells. LRWD1 had been previously described as a testis specific gene with only limited information on its function. Analysis of LRWD1 mRNA levels in patient samples indicated that high expression associated with poor overall survival in Ewing sarcoma. Gene ontology analysis of LRWD1 co-expressed genes in Ewing tumors revealed association with DNA replication and analysis of differentially expressed genes in LRWD1 depleted Ewing sarcoma cells indicated a role in connective tissue development and cellular morphogenesis. Moreover, EWS-FLI1 repressed genes with repressive H3K27me3 chromatin marks were highly enriched among LRWD1 target genes in A673/TR/shEF Ewing sarcoma cells, suggesting that LRWD1 contributes to EWS-FLI1 driven transcriptional regulation. Taken together, we have identified LRWD1 as a novel regulator of EWS-FLI1 driven cell viability in A673/TR/shEF Ewing sarcoma cells, shown association between high LRWD1 mRNA expression and aggressive disease and identified processes by which LRWD1 may promote oncogenesis in Ewing sarcoma.

Replier
Claire Provost, Aurélie Prignon, Alex Cazes, Valérie Combaret, Olivier Delattre, Isabelle Janoueix-Lerosey, Françoise Montravers, Jean-Noël Talbot (2016 Sep 16)

68Ga-DOTATOC and FDG PET Imaging of Preclinical Neuroblastoma Models.

Anticancer research : 4459-66 En savoir plus
Résumé

Somatostatine receptors subtype 2 (SSTR2) are regarded as a potential target in neuroblastoma (NB) for imaging and promising therapeutic approaches. The purpose of this study was to evaluate and compare the SSTR2 status by (68)Ga-[tetraxetan-D-Phe1, Tyr3]-octreotide ((68)Ga-DOTATOC) positron-emission tomography (PET) and the tumour metabolic activity by (18)F-fluorodeoxyglucose (FDG) PET in different experimental models of NB.

Replier
Mathieu Chicard, Sandrine Boyault, Leo Colmet Daage, Wilfrid Richer, David Gentien, Gaelle Pierron, Eve Lapouble, Angela Bellini, Nathalie Clement, Isabelle Iacono, Stéphanie Bréjon, Marjorie Carrere, Cécile Reyes, Toby Hocking, Virginie Bernard, Michel Peuchmaur, Nadège Corradini, Cécile Faure-Conter, Carole Coze, Dominique Plantaz, Anne Sophie Defachelles, Estelle Thebaud, Marion Gambart, Frédéric Millot, Dominique Valteau-Couanet, Jean Michon, Alain Puisieux, Olivier Delattre, Valérie Combaret, Gudrun Schleiermacher (2016 Jul 22)

Genomic copy number profiling using circulating free tumor DNA highlights heterogeneity in neuroblastoma.

Clinical cancer research : an official journal of the American Association for Cancer Research : DOI : clincanres.0500.2016 En savoir plus
Résumé

The tumor genomic copy number profile is of prognostic significance in neuroblastoma (NB) patients. We have studied the genomic copy number profile of cell free DNA (cfDNA) and compared this to primary tumor aCGH at diagnosis.

Replier
Tsion Zewdu Minas, Didier Surdez, Tahereh Javaheri, Miwa Tanaka, Michelle Howarth, Hong-Jun Kang, Jenny Han, Zhi-Yan Han, Barbara Sax, Barbara E Kream, Sung-Hyeok Hong, Haydar Çelik, Franck Tirode, Jan Tuckermann, Jeffrey A Toretsky, Lukas Kenner, Heinrich Kovar, Sean Lee, E Alejandro Sweet-Cordero, Takuro Nakamura, Richard Moriggl, Olivier Delattre, Aykut Üren (2016 May 19)

Combined experience of six independent laboratories attempting to create an Ewing sarcoma mouse model.

Oncotarget : DOI : 10.18632/oncotarget.9388 En savoir plus
Résumé

Ewing sarcoma (ES) involves a tumor-specific chromosomal translocation that produces the EWS-FLI1 protein, which is required for the growth of ES cells both in vitro and in vivo. However, an EWS-FLI1-driven transgenic mouse model is not currently available. Here, we present data from six independent laboratories seeking an alternative approach to express EWS-FLI1 in different murine tissues. We used the Runx2, Col1a2.3, Col1a3.6, Prx1, CAG, Nse, NEFL, Dermo1, P0, Sox9 and Osterix promoters to target EWS-FLI1 or Cre expression. Additional approaches included the induction of an endogenous chromosomal translocation, in utero knock-in, and the injection of Cre-expressing adenovirus to induce EWS-FLI1 expression locally in multiple lineages. Most models resulted in embryonic lethality or developmental defects. EWS-FLI1-induced apoptosis, promoter leakiness, the lack of potential cofactors, and the difficulty of expressing EWS-FLI1 in specific sites were considered the primary reasons for the failed attempts to create a transgenic mouse model of ES.

Replier
Thomas G P Grünewald, Pascale Gilardi-Hebenstreit, Patrick Charnay, Olivier Delattre (2016 May 4)

[Cooperation between a somatic mutation and a genetic susceptibility variant in Ewing sarcoma].

Médecine sciences : M/S : 323-6 : DOI : 10.1051/medsci/20163204004 En savoir plus
Résumé

Replier
Navin Pinto, Jodi R Mayfield, Gordana Raca, Mark A Applebaum, Alexandre Chlenski, Madina Sukhanova, Rochelle Bagatell, Meredith S Irwin, Anthony Little, Jawhar Rawwas, Yasmin Gosiengfiao, Olivier Delattre, Isabelle Janoueix-Lerosey, Eve Lapouble, Gudrun Schleiermacher, Susan L Cohn (2016 Feb 12)

Segmental Chromosomal Aberrations in Localized Neuroblastoma Can be Detected in Formalin-Fixed Paraffin-Embedded Tissue Samples and Are Associated With Recurrence.

Pediatric blood & cancer : 1019-23 : DOI : 10.1002/pbc.25934 En savoir plus
Résumé

Array comparative genomic hybridization (CGH) analyses of frozen tumors have shown strong associations between the pattern of chromosomal aberrations and outcome in patients with advanced-stage neuroblastoma. New platforms for analyzing chromosomal aberrations using formalin-fixed paraffin-embedded (FFPE) tissue have recently been developed. We sought to determine whether chromosomal microarray analysis (CMA) using FFPE tumors is feasible and if segmental chromosomal aberrations were prognostic of recurrence in localized neuroblastoma.

Replier
Zhi-Yan Han, Wilfrid Richer, Paul Fréneaux, Céline Chauvin, Carlo Lucchesi, Delphine Guillemot, Camille Grison, Delphine Lequin, Gaelle Pierron, Julien Masliah-Planchon, André Nicolas, Dominique Ranchère-Vince, Pascale Varlet, Stéphanie Puget, Isabelle Janoueix-Lerosey, Olivier Ayrault, Didier Surdez, Olivier Delattre, Franck Bourdeaut (2016 Jan 29)

The occurrence of intracranial rhabdoid tumours in mice depends on temporal control of Smarcb1 inactivation.

Nature communications : 10421 : DOI : 10.1038/ncomms10421 En savoir plus
Résumé

Rhabdoid tumours (RTs) are highly aggressive tumours of infancy, frequently localized in the central nervous system (CNS) where they are termed atypical teratoid/rhabdoid tumours (AT/RTs) and characterized by bi-allelic inactivation of the SMARCB1 tumour suppressor gene. In this study, by temporal control of tamoxifen injection in Smarcb1(flox/flox);Rosa26-Cre(ERT2) mice, we explore the phenotypes associated with Smarcb1 inactivation at different developmental stages. Injection before E6, at birth or at 2 months of age recapitulates previously described phenotypes including embryonic lethality, hepatic toxicity or development of T-cell lymphomas, respectively. Injection between E6 and E10 leads to high penetrance tumours, mainly intra-cranial, with short delays (median: 3 months). These tumours demonstrate anatomical, morphological and gene expression profiles consistent with those of human AT/RTs. Moreover, intra- and inter-species comparisons of tumours reveal that human and mouse RTs can be split into different entities that may underline the variety of RT cells of origin.

Replier