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1. Oncogenic ETS fusions promote DNA damage and proinflammatory responses via pericentromeric RNAs in extracellular vesicles.

Author

Ruzanov, Peter, Evdokimova, Valentina, Pachva, Manideep, Minkovich, Alon, Zhang, Zhenbo, Langman, Sofya, Gassmann, Hendrik, Thiel, Uwe, Orlic-Milacic, Marija, Zaidi, Syed, Peltekova, Vanya, Heisler, Lawrence, Sharma, Manju, Cox, Michael, McKee, Trevor, Zaidi, Mark, Lapouble, Eve, Delattre, Olivier, Radvanyi, Laszlo, Burdach, Stefan, Stein, Lincoln, Sorensen, Poul, and Mcpherson, John

Subjects
Inflammation, Innate immunity, Humans, Extracellular Vesicles, DNA Damage, Oncogene Proteins, Fusion, Transcriptional Regulator ERG, Male, RNA-Binding Protein EWS, Proto-Oncogene Protein c-fli-1, Sarcoma, Ewing, Cell Line, Tumor, RNA, Neoplasm, Inflammation, Prostatic Neoplasms, Mice, Animals, Heterochromatin
Abstract

Aberrant expression of the E26 transformation-specific (ETS) transcription factors characterizes numerous human malignancies. Many of these proteins, including EWS:FLI1 and EWS:ERG fusions in Ewing sarcoma (EwS) and TMPRSS2:ERG in prostate cancer (PCa), drive oncogenic programs via binding to GGAA repeats. We report here that both EWS:FLI1 and ERG bind and transcriptionally activate GGAA-rich pericentromeric heterochromatin. The respective pathogen-like HSAT2 and HSAT3 RNAs, together with LINE, SINE, ERV, and other repeat transcripts, are expressed in EwS and PCa tumors, secreted in extracellular vesicles (EVs), and are highly elevated in plasma of patients with EwS with metastatic disease. High human satellite 2 and 3 (HSAT2,3) levels in EWS:FLI1- or ERG-expressing cells and tumors were associated with induction of G2/M checkpoint, mitotic spindle, and DNA damage programs. These programs were also activated in EwS EV-treated fibroblasts, coincident with accumulation of HSAT2,3 RNAs, proinflammatory responses, mitotic defects, and senescence. Mechanistically, HSAT2,3-enriched cancer EVs induced cGAS-TBK1 innate immune signaling and formation of cytosolic granules positive for double-strand RNAs, RNA-DNA, and cGAS. Hence, aberrantly expressed ETS proteins derepress pericentromeric heterochromatin, yielding pathogenic RNAs that transmit genotoxic stress and inflammation to local and distant sites. Monitoring HSAT2,3 plasma levels and preventing their dissemination may thus improve therapeutic strategies and blood-based diagnostics.

Published
2024

2. Impact of age on survival according to molecular tumor findings in children and adolescents with soft-tissue and bone sarcoma: The BIOSCA project

Author

Desandes, Emmanuel, Lapouble, Eve, Lacour, Brigitte, Guissou, Sandra, Goujon, Stéphanie, Defachelles, Anne-Sophie, Marechal, Valérie, Gaspar, Nathalie, Gomez-Mascard, Anne, Karanian, Marie, Marec-Berard, Perrine, Minard-Colin, Véronique, Orbach, Daniel, Tabone, Marie-Dominique, Delattre, Olivier, and Pierron, Gaelle

Published
2024
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3. Reversible transitions between noradrenergic and mesenchymal tumor identities define cell plasticity in neuroblastoma

Author

Thirant, Cécile, Peltier, Agathe, Durand, Simon, Kramdi, Amira, Louis-Brennetot, Caroline, Pierre-Eugène, Cécile, Gautier, Margot, Costa, Ana, Grelier, Amandine, Zaïdi, Sakina, Gruel, Nadège, Jimenez, Irène, Lapouble, Eve, Pierron, Gaëlle, Sitbon, Déborah, Brisse, Hervé J., Gauthier, Arnaud, Fréneaux, Paul, Grossetête, Sandrine, Baudrin, Laura G., Raynal, Virginie, Baulande, Sylvain, Bellini, Angela, Bhalshankar, Jaydutt, Carcaboso, Angel M., Geoerger, Birgit, Rohrer, Hermann, Surdez, Didier, Boeva, Valentina, Schleiermacher, Gudrun, Delattre, Olivier, and Janoueix-Lerosey, Isabelle

Published
2023
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4. Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus identifies germline-somatic interactions with EWSR1-FLI1 binding

Author

Lee, Olivia W., Rodrigues, Calvin, Lin, Shu-Hong, Luo, Wen, Jones, Kristine, Brown, Derek W., Zhou, Weiyin, Karlins, Eric, Khan, Sairah M., Baulande, Sylvain, Raynal, Virginie, Surdez, Didier, Reynaud, Stephanie, Rubio, Rebeca Alba, Zaidi, Sakina, Grossetête, Sandrine, Ballet, Stelly, Lapouble, Eve, Laurence, Valérie, Pierron, Gaelle, Gaspar, Nathalie, Corradini, Nadège, Marec-Bérard, Perrine, Rothman, Nathaniel, Dagnall, Casey L., Burdett, Laurie, Manning, Michelle, Wyatt, Kathleen, Yeager, Meredith, Chari, Raj, Leisenring, Wendy M., Kulozik, Andreas E., Kriebel, Jennifer, Meitinger, Thomas, Strauch, Konstantin, Kirchner, Thomas, Dirksen, Uta, Mirabello, Lisa, Tucker, Margaret A., Tirode, Franck, Armstrong, Gregory T., Bhatia, Smita, Robison, Leslie L., Yasui, Yutaka, Romero-Pérez, Laura, Hartmann, Wolfgang, Metzler, Markus, Diver, W. Ryan, Lori, Adriana, Freedman, Neal D., Hoover, Robert N., Morton, Lindsay M., Chanock, Stephen J., Grünewald, Thomas G.P., Delattre, Olivier, and Machiela, Mitchell J.

Published
2023
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5. Molecular diagnosis of retinoblastoma by circulating tumor DNA analysis

Author

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

Published
2021
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6. Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden

Author

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

Published
2021
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7. Supplementary Table 1 from Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 Mutations

Author

Tirode, Franck, primary, Surdez, Didier, primary, Ma, Xiaotu, primary, Parker, Matthew, primary, Le Deley, Marie Cécile, primary, Bahrami, Armita, primary, Zhang, Zhaojie, primary, Lapouble, Eve, primary, Grossetête-Lalami, Sandrine, primary, Rusch, Michael, primary, Reynaud, Stéphanie, primary, Rio-Frio, Thomas, primary, Hedlund, Erin, primary, Wu, Gang, primary, Chen, Xiang, primary, Pierron, Gaelle, primary, Oberlin, Odile, primary, Zaidi, Sakina, primary, Lemmon, Gordon, primary, Gupta, Pankaj, primary, Vadodaria, Bhavin, primary, Easton, John, primary, Gut, Marta, primary, Ding, Li, primary, Mardis, Elaine R., primary, Wilson, Richard K., primary, Shurtleff, Sheila, primary, Laurence, Valérie, primary, Michon, Jean, primary, Marec-Bérard, Perrine, primary, Gut, Ivo, primary, Downing, James, primary, Dyer, Michael, primary, Zhang, Jinghui, primary, and Delattre, Olivier, primary

Published
2023
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8. Supplementary Table 4 from Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 Mutations

Author

Tirode, Franck, primary, Surdez, Didier, primary, Ma, Xiaotu, primary, Parker, Matthew, primary, Le Deley, Marie Cécile, primary, Bahrami, Armita, primary, Zhang, Zhaojie, primary, Lapouble, Eve, primary, Grossetête-Lalami, Sandrine, primary, Rusch, Michael, primary, Reynaud, Stéphanie, primary, Rio-Frio, Thomas, primary, Hedlund, Erin, primary, Wu, Gang, primary, Chen, Xiang, primary, Pierron, Gaelle, primary, Oberlin, Odile, primary, Zaidi, Sakina, primary, Lemmon, Gordon, primary, Gupta, Pankaj, primary, Vadodaria, Bhavin, primary, Easton, John, primary, Gut, Marta, primary, Ding, Li, primary, Mardis, Elaine R., primary, Wilson, Richard K., primary, Shurtleff, Sheila, primary, Laurence, Valérie, primary, Michon, Jean, primary, Marec-Bérard, Perrine, primary, Gut, Ivo, primary, Downing, James, primary, Dyer, Michael, primary, Zhang, Jinghui, primary, and Delattre, Olivier, primary

Published
2023
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9. Supplementary Table 2 from Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 Mutations

Author

Tirode, Franck, primary, Surdez, Didier, primary, Ma, Xiaotu, primary, Parker, Matthew, primary, Le Deley, Marie Cécile, primary, Bahrami, Armita, primary, Zhang, Zhaojie, primary, Lapouble, Eve, primary, Grossetête-Lalami, Sandrine, primary, Rusch, Michael, primary, Reynaud, Stéphanie, primary, Rio-Frio, Thomas, primary, Hedlund, Erin, primary, Wu, Gang, primary, Chen, Xiang, primary, Pierron, Gaelle, primary, Oberlin, Odile, primary, Zaidi, Sakina, primary, Lemmon, Gordon, primary, Gupta, Pankaj, primary, Vadodaria, Bhavin, primary, Easton, John, primary, Gut, Marta, primary, Ding, Li, primary, Mardis, Elaine R., primary, Wilson, Richard K., primary, Shurtleff, Sheila, primary, Laurence, Valérie, primary, Michon, Jean, primary, Marec-Bérard, Perrine, primary, Gut, Ivo, primary, Downing, James, primary, Dyer, Michael, primary, Zhang, Jinghui, primary, and Delattre, Olivier, primary

Published
2023
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10. Data from Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 Mutations

Author

Tirode, Franck, primary, Surdez, Didier, primary, Ma, Xiaotu, primary, Parker, Matthew, primary, Le Deley, Marie Cécile, primary, Bahrami, Armita, primary, Zhang, Zhaojie, primary, Lapouble, Eve, primary, Grossetête-Lalami, Sandrine, primary, Rusch, Michael, primary, Reynaud, Stéphanie, primary, Rio-Frio, Thomas, primary, Hedlund, Erin, primary, Wu, Gang, primary, Chen, Xiang, primary, Pierron, Gaelle, primary, Oberlin, Odile, primary, Zaidi, Sakina, primary, Lemmon, Gordon, primary, Gupta, Pankaj, primary, Vadodaria, Bhavin, primary, Easton, John, primary, Gut, Marta, primary, Ding, Li, primary, Mardis, Elaine R., primary, Wilson, Richard K., primary, Shurtleff, Sheila, primary, Laurence, Valérie, primary, Michon, Jean, primary, Marec-Bérard, Perrine, primary, Gut, Ivo, primary, Downing, James, primary, Dyer, Michael, primary, Zhang, Jinghui, primary, and Delattre, Olivier, primary

Published
2023
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11. Supplementary Table and Figure Legends from Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 Mutations

Author

Tirode, Franck, primary, Surdez, Didier, primary, Ma, Xiaotu, primary, Parker, Matthew, primary, Le Deley, Marie Cécile, primary, Bahrami, Armita, primary, Zhang, Zhaojie, primary, Lapouble, Eve, primary, Grossetête-Lalami, Sandrine, primary, Rusch, Michael, primary, Reynaud, Stéphanie, primary, Rio-Frio, Thomas, primary, Hedlund, Erin, primary, Wu, Gang, primary, Chen, Xiang, primary, Pierron, Gaelle, primary, Oberlin, Odile, primary, Zaidi, Sakina, primary, Lemmon, Gordon, primary, Gupta, Pankaj, primary, Vadodaria, Bhavin, primary, Easton, John, primary, Gut, Marta, primary, Ding, Li, primary, Mardis, Elaine R., primary, Wilson, Richard K., primary, Shurtleff, Sheila, primary, Laurence, Valérie, primary, Michon, Jean, primary, Marec-Bérard, Perrine, primary, Gut, Ivo, primary, Downing, James, primary, Dyer, Michael, primary, Zhang, Jinghui, primary, and Delattre, Olivier, primary

Published
2023
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12. Supplementary Table 3 from Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 Mutations

Author

Tirode, Franck, primary, Surdez, Didier, primary, Ma, Xiaotu, primary, Parker, Matthew, primary, Le Deley, Marie Cécile, primary, Bahrami, Armita, primary, Zhang, Zhaojie, primary, Lapouble, Eve, primary, Grossetête-Lalami, Sandrine, primary, Rusch, Michael, primary, Reynaud, Stéphanie, primary, Rio-Frio, Thomas, primary, Hedlund, Erin, primary, Wu, Gang, primary, Chen, Xiang, primary, Pierron, Gaelle, primary, Oberlin, Odile, primary, Zaidi, Sakina, primary, Lemmon, Gordon, primary, Gupta, Pankaj, primary, Vadodaria, Bhavin, primary, Easton, John, primary, Gut, Marta, primary, Ding, Li, primary, Mardis, Elaine R., primary, Wilson, Richard K., primary, Shurtleff, Sheila, primary, Laurence, Valérie, primary, Michon, Jean, primary, Marec-Bérard, Perrine, primary, Gut, Ivo, primary, Downing, James, primary, Dyer, Michael, primary, Zhang, Jinghui, primary, and Delattre, Olivier, primary

Published
2023
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13. Supplementary Table 5 from Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 Mutations

Author

Tirode, Franck, primary, Surdez, Didier, primary, Ma, Xiaotu, primary, Parker, Matthew, primary, Le Deley, Marie Cécile, primary, Bahrami, Armita, primary, Zhang, Zhaojie, primary, Lapouble, Eve, primary, Grossetête-Lalami, Sandrine, primary, Rusch, Michael, primary, Reynaud, Stéphanie, primary, Rio-Frio, Thomas, primary, Hedlund, Erin, primary, Wu, Gang, primary, Chen, Xiang, primary, Pierron, Gaelle, primary, Oberlin, Odile, primary, Zaidi, Sakina, primary, Lemmon, Gordon, primary, Gupta, Pankaj, primary, Vadodaria, Bhavin, primary, Easton, John, primary, Gut, Marta, primary, Ding, Li, primary, Mardis, Elaine R., primary, Wilson, Richard K., primary, Shurtleff, Sheila, primary, Laurence, Valérie, primary, Michon, Jean, primary, Marec-Bérard, Perrine, primary, Gut, Ivo, primary, Downing, James, primary, Dyer, Michael, primary, Zhang, Jinghui, primary, and Delattre, Olivier, primary

Published
2023
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14. Supplementary Figures 1 - 5 from Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 Mutations

Author

Tirode, Franck, primary, Surdez, Didier, primary, Ma, Xiaotu, primary, Parker, Matthew, primary, Le Deley, Marie Cécile, primary, Bahrami, Armita, primary, Zhang, Zhaojie, primary, Lapouble, Eve, primary, Grossetête-Lalami, Sandrine, primary, Rusch, Michael, primary, Reynaud, Stéphanie, primary, Rio-Frio, Thomas, primary, Hedlund, Erin, primary, Wu, Gang, primary, Chen, Xiang, primary, Pierron, Gaelle, primary, Oberlin, Odile, primary, Zaidi, Sakina, primary, Lemmon, Gordon, primary, Gupta, Pankaj, primary, Vadodaria, Bhavin, primary, Easton, John, primary, Gut, Marta, primary, Ding, Li, primary, Mardis, Elaine R., primary, Wilson, Richard K., primary, Shurtleff, Sheila, primary, Laurence, Valérie, primary, Michon, Jean, primary, Marec-Bérard, Perrine, primary, Gut, Ivo, primary, Downing, James, primary, Dyer, Michael, primary, Zhang, Jinghui, primary, and Delattre, Olivier, primary

Published
2023
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15. Supplementary Figure 2 from Deep Sequencing Reveals Occurrence of Subclonal ALK Mutations in Neuroblastoma at Diagnosis

Author

Bellini, Angela, primary, Bernard, Virginie, primary, Leroy, Quentin, primary, Rio Frio, Thomas, primary, Pierron, Gaelle, primary, Combaret, Valérie, primary, Lapouble, Eve, primary, Clement, Nathalie, primary, Rubie, Herve, primary, Thebaud, Estelle, primary, Chastagner, Pascal, primary, Defachelles, Anne Sophie, primary, Bergeron, Christophe, primary, Buchbinder, Nimrod, primary, Taque, Sophie, primary, Auvrignon, Anne, primary, Valteau-Couanet, Dominique, primary, Michon, Jean, primary, Janoueix-Lerosey, Isabelle, primary, Delattre, Olivier, primary, and Schleiermacher, Gudrun, primary

Published
2023
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16. supplemental figure legend from Deep Sequencing Reveals Occurrence of Subclonal ALK Mutations in Neuroblastoma at Diagnosis

Author

Bellini, Angela, primary, Bernard, Virginie, primary, Leroy, Quentin, primary, Rio Frio, Thomas, primary, Pierron, Gaelle, primary, Combaret, Valérie, primary, Lapouble, Eve, primary, Clement, Nathalie, primary, Rubie, Herve, primary, Thebaud, Estelle, primary, Chastagner, Pascal, primary, Defachelles, Anne Sophie, primary, Bergeron, Christophe, primary, Buchbinder, Nimrod, primary, Taque, Sophie, primary, Auvrignon, Anne, primary, Valteau-Couanet, Dominique, primary, Michon, Jean, primary, Janoueix-Lerosey, Isabelle, primary, Delattre, Olivier, primary, and Schleiermacher, Gudrun, primary

Published
2023
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17. Supplemental Figure 4 from Genomic Copy Number Profiling Using Circulating Free Tumor DNA Highlights Heterogeneity in Neuroblastoma

Author

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

Published
2023
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18. Supplemental Patient Information from Genomic Copy Number Profiling Using Circulating Free Tumor DNA Highlights Heterogeneity in Neuroblastoma

Author

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

Published
2023
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19. Supplemental Figure 3 from Genomic Copy Number Profiling Using Circulating Free Tumor DNA Highlights Heterogeneity in Neuroblastoma

Author

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

Published
2023
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20. Supplementary Figure Legends, Supplementary Figures 1-8, Supplementary References, Supplemental Information (1) on treatment protocols from Whole-Exome Sequencing of Cell-Free DNA Reveals Temporo-spatial Heterogeneity and Identifies Treatment-Resistant Clones in Neuroblastoma

Author

Chicard, Mathieu, primary, Colmet-Daage, Leo, primary, Clement, Nathalie, primary, Danzon, Adrien, primary, Bohec, Mylène, primary, Bernard, Virginie, primary, Baulande, Sylvain, primary, Bellini, Angela, primary, Deveau, Paul, primary, Pierron, Gaëlle, primary, Lapouble, Eve, primary, Janoueix-Lerosey, Isabelle, primary, Peuchmaur, Michel, primary, Corradini, Nadège, primary, Defachelles, Anne Sophie, primary, Valteau-Couanet, Dominique, primary, Michon, Jean, primary, Combaret, Valérie, primary, Delattre, Olivier, primary, and Schleiermacher, Gudrun, primary

Published
2023
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21. Supplementary Table 2 from Deep Sequencing Reveals Occurrence of Subclonal ALK Mutations in Neuroblastoma at Diagnosis

Author

Bellini, Angela, primary, Bernard, Virginie, primary, Leroy, Quentin, primary, Rio Frio, Thomas, primary, Pierron, Gaelle, primary, Combaret, Valérie, primary, Lapouble, Eve, primary, Clement, Nathalie, primary, Rubie, Herve, primary, Thebaud, Estelle, primary, Chastagner, Pascal, primary, Defachelles, Anne Sophie, primary, Bergeron, Christophe, primary, Buchbinder, Nimrod, primary, Taque, Sophie, primary, Auvrignon, Anne, primary, Valteau-Couanet, Dominique, primary, Michon, Jean, primary, Janoueix-Lerosey, Isabelle, primary, Delattre, Olivier, primary, and Schleiermacher, Gudrun, primary

Published
2023
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22. Supplementary Table 3 from Whole-Exome Sequencing of Cell-Free DNA Reveals Temporo-spatial Heterogeneity and Identifies Treatment-Resistant Clones in Neuroblastoma

Author

Chicard, Mathieu, primary, Colmet-Daage, Leo, primary, Clement, Nathalie, primary, Danzon, Adrien, primary, Bohec, Mylène, primary, Bernard, Virginie, primary, Baulande, Sylvain, primary, Bellini, Angela, primary, Deveau, Paul, primary, Pierron, Gaëlle, primary, Lapouble, Eve, primary, Janoueix-Lerosey, Isabelle, primary, Peuchmaur, Michel, primary, Corradini, Nadège, primary, Defachelles, Anne Sophie, primary, Valteau-Couanet, Dominique, primary, Michon, Jean, primary, Combaret, Valérie, primary, Delattre, Olivier, primary, and Schleiermacher, Gudrun, primary

Published
2023
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23. Supplemental Figure 5 from Genomic Copy Number Profiling Using Circulating Free Tumor DNA Highlights Heterogeneity in Neuroblastoma

Author

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

Published
2023
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24. Supplemental Table 1 from Genomic Copy Number Profiling Using Circulating Free Tumor DNA Highlights Heterogeneity in Neuroblastoma

Author

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

Published
2023
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25. Supplemental Figure 2 from Genomic Copy Number Profiling Using Circulating Free Tumor DNA Highlights Heterogeneity in Neuroblastoma

Author

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

Published
2023
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26. Supplementary Table 1 from Deep Sequencing Reveals Occurrence of Subclonal ALK Mutations in Neuroblastoma at Diagnosis

Author

Bellini, Angela, primary, Bernard, Virginie, primary, Leroy, Quentin, primary, Rio Frio, Thomas, primary, Pierron, Gaelle, primary, Combaret, Valérie, primary, Lapouble, Eve, primary, Clement, Nathalie, primary, Rubie, Herve, primary, Thebaud, Estelle, primary, Chastagner, Pascal, primary, Defachelles, Anne Sophie, primary, Bergeron, Christophe, primary, Buchbinder, Nimrod, primary, Taque, Sophie, primary, Auvrignon, Anne, primary, Valteau-Couanet, Dominique, primary, Michon, Jean, primary, Janoueix-Lerosey, Isabelle, primary, Delattre, Olivier, primary, and Schleiermacher, Gudrun, primary

Published
2023
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27. Supplemental Table 2 from Genomic Copy Number Profiling Using Circulating Free Tumor DNA Highlights Heterogeneity in Neuroblastoma

Author

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

Published
2023
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28. Supplementary Figure 1 from Deep Sequencing Reveals Occurrence of Subclonal ALK Mutations in Neuroblastoma at Diagnosis

Author

Bellini, Angela, primary, Bernard, Virginie, primary, Leroy, Quentin, primary, Rio Frio, Thomas, primary, Pierron, Gaelle, primary, Combaret, Valérie, primary, Lapouble, Eve, primary, Clement, Nathalie, primary, Rubie, Herve, primary, Thebaud, Estelle, primary, Chastagner, Pascal, primary, Defachelles, Anne Sophie, primary, Bergeron, Christophe, primary, Buchbinder, Nimrod, primary, Taque, Sophie, primary, Auvrignon, Anne, primary, Valteau-Couanet, Dominique, primary, Michon, Jean, primary, Janoueix-Lerosey, Isabelle, primary, Delattre, Olivier, primary, and Schleiermacher, Gudrun, primary

Published
2023
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29. Reversible transitions between noradrenergic and mesenchymal tumor identities define cell plasticity in neuroblastoma

Author

Thirant, Cécile; https://orcid.org/0000-0003-3873-5240, Peltier, Agathe; https://orcid.org/0000-0003-0017-277X, Durand, Simon; https://orcid.org/0000-0003-1748-7655, Kramdi, Amira, Louis-Brennetot, Caroline; https://orcid.org/0000-0002-4952-3828, Pierre-Eugène, Cécile, Gautier, Margot; https://orcid.org/0000-0003-4028-3466, Costa, Ana; https://orcid.org/0000-0002-0893-3388, Grelier, Amandine, Zaïdi, Sakina; https://orcid.org/0000-0001-9128-0287, Gruel, Nadège, Jimenez, Irène; https://orcid.org/0000-0002-3544-4045, Lapouble, Eve; https://orcid.org/0000-0003-3374-3671, Pierron, Gaëlle; https://orcid.org/0000-0002-2536-7680, Sitbon, Déborah, Brisse, Hervé J; https://orcid.org/0000-0003-2794-5875, Gauthier, Arnaud, Fréneaux, Paul, Grossetête, Sandrine, Baudrin, Laura G, Raynal, Virginie, Baulande, Sylvain, Bellini, Angela, Bhalshankar, Jaydutt, Carcaboso, Angel M; https://orcid.org/0000-0002-8485-426X, Geoerger, Birgit; https://orcid.org/0000-0003-4361-3643, Rohrer, Hermann; https://orcid.org/0000-0001-7023-1355, Surdez, Didier; https://orcid.org/0000-0002-7118-7859, Boeva, Valentina; https://orcid.org/0000-0002-4382-7185, Schleiermacher, Gudrun; https://orcid.org/0000-0002-0133-5879, et al, Thirant, Cécile; https://orcid.org/0000-0003-3873-5240, Peltier, Agathe; https://orcid.org/0000-0003-0017-277X, Durand, Simon; https://orcid.org/0000-0003-1748-7655, Kramdi, Amira, Louis-Brennetot, Caroline; https://orcid.org/0000-0002-4952-3828, Pierre-Eugène, Cécile, Gautier, Margot; https://orcid.org/0000-0003-4028-3466, Costa, Ana; https://orcid.org/0000-0002-0893-3388, Grelier, Amandine, Zaïdi, Sakina; https://orcid.org/0000-0001-9128-0287, Gruel, Nadège, Jimenez, Irène; https://orcid.org/0000-0002-3544-4045, Lapouble, Eve; https://orcid.org/0000-0003-3374-3671, Pierron, Gaëlle; https://orcid.org/0000-0002-2536-7680, Sitbon, Déborah, Brisse, Hervé J; https://orcid.org/0000-0003-2794-5875, Gauthier, Arnaud, Fréneaux, Paul, Grossetête, Sandrine, Baudrin, Laura G, Raynal, Virginie, Baulande, Sylvain, Bellini, Angela, Bhalshankar, Jaydutt, Carcaboso, Angel M; https://orcid.org/0000-0002-8485-426X, Geoerger, Birgit; https://orcid.org/0000-0003-4361-3643, Rohrer, Hermann; https://orcid.org/0000-0001-7023-1355, Surdez, Didier; https://orcid.org/0000-0002-7118-7859, Boeva, Valentina; https://orcid.org/0000-0002-4382-7185, Schleiermacher, Gudrun; https://orcid.org/0000-0002-0133-5879, and et al

Abstract

Noradrenergic and mesenchymal identities have been characterized in neuroblastoma cell lines according to their epigenetic landscapes and core regulatory circuitries. However, their relationship and relative contribution in patient tumors remain poorly defined. We now document spontaneous and reversible plasticity between the two identities, associated with epigenetic reprogramming, in several neuroblastoma models. Interestingly, xenografts with cells from each identity eventually harbor a noradrenergic phenotype suggesting that the microenvironment provides a powerful pressure towards this phenotype. Accordingly, such a noradrenergic cell identity is systematically observed in single-cell RNA-seq of 18 tumor biopsies and 15 PDX models. Yet, a subpopulation of these noradrenergic tumor cells presents with mesenchymal features that are shared with plasticity models, indicating that the plasticity described in these models has relevance in neuroblastoma patients. This work therefore emphasizes that intrinsic plasticity properties of neuroblastoma cells are dependent upon external cues of the environment to drive cell identity.

Published
2023

30. Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus identifies germline-somatic interactions with EWSR1-FLI1 binding

Author

Lee, Olivia W, Rodrigues, Calvin, Lin, Shu-Hong, Luo, Wen, Jones, Kristine, Brown, Derek W, Zhou, Weiyin, Karlins, Eric, Khan, Sairah M, Baulande, Sylvain, Raynal, Virginie, Surdez, Didier; https://orcid.org/0000-0002-7118-7859, Reynaud, Stephanie, Rubio, Rebeca Alba, Zaidi, Sakina, Grossetête, Sandrine, Ballet, Stelly, Lapouble, Eve, Laurence, Valérie, Pierron, Gaelle, Gaspar, Nathalie, Corradini, Nadège, Marec-Bérard, Perrine, Rothman, Nathaniel, Dagnall, Casey L, Burdett, Laurie, Manning, Michelle, Wyatt, Kathleen, Yeager, Meredith, Chari, Raj, et al, Lee, Olivia W, Rodrigues, Calvin, Lin, Shu-Hong, Luo, Wen, Jones, Kristine, Brown, Derek W, Zhou, Weiyin, Karlins, Eric, Khan, Sairah M, Baulande, Sylvain, Raynal, Virginie, Surdez, Didier; https://orcid.org/0000-0002-7118-7859, Reynaud, Stephanie, Rubio, Rebeca Alba, Zaidi, Sakina, Grossetête, Sandrine, Ballet, Stelly, Lapouble, Eve, Laurence, Valérie, Pierron, Gaelle, Gaspar, Nathalie, Corradini, Nadège, Marec-Bérard, Perrine, Rothman, Nathaniel, Dagnall, Casey L, Burdett, Laurie, Manning, Michelle, Wyatt, Kathleen, Yeager, Meredith, Chari, Raj, and et al

Abstract

Ewing sarcoma (EwS) is a rare bone and soft tissue malignancy driven by chromosomal translocations encoding chimeric transcription factors, such as EWSR1-FLI1, that bind GGAA motifs forming novel enhancers that alter nearby expression. We propose that germline microsatellite variation at the 6p25.1 EwS susceptibility locus could impact downstream gene expression and EwS biology. We performed targeted long-read sequencing of EwS blood DNA to characterize variation and genomic features important for EWSR1-FLI1 binding. We identified 50 microsatellite alleles at 6p25.1 and observed that EwS-affected individuals had longer alleles (>135 bp) with more GGAA repeats. The 6p25.1 GGAA microsatellite showed chromatin features of an EWSR1-FLI1 enhancer and regulated expression of RREB1, a transcription factor associated with RAS/MAPK signaling. RREB1 knockdown reduced proliferation and clonogenic potential and reduced expression of cell cycle and DNA replication genes. Our integrative analysis at 6p25.1 details increased binding of longer GGAA microsatellite alleles with acquired EWSR-FLI1 to promote Ewing sarcomagenesis by RREB1-mediated proliferation.

Published
2023

32. DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma

Author

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

Subjects
Methylation -- Health aspects, Cancer cells -- Genetic aspects, Ewing's sarcoma -- Genetic aspects, Biological sciences, Health
Abstract

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., Author(s): Nathan C Sheffield [1]; Gaelle Pierron [2]; Johanna Klughammer [1]; Paul Datlinger [1]; Andreas Schönegger [1]; Michael Schuster [1]; Johanna Hadler [1]; Didier Surdez [3]; Delphine Guillemot [2]; Eve [...]

Published
2017
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33. Single-cell transcriptomics reveals shared immunosuppressive landscapes of mouse and human neuroblastoma

Author

Costa, Ana, primary, Thirant, Cécile, additional, Kramdi, Amira, additional, Pierre-Eugène, Cécile, additional, Louis-Brennetot, Caroline, additional, Blanchard, Orphée, additional, Surdez, Didier, additional, Gruel, Nadege, additional, Lapouble, Eve, additional, Pierron, Gaëlle, additional, Sitbon, Deborah, additional, Brisse, Hervé, additional, Gauthier, Arnaud, additional, Fréneaux, Paul, additional, Bohec, Mylène, additional, Raynal, Virginie, additional, Baulande, Sylvain, additional, Leclere, Renaud, additional, Champenois, Gabriel, additional, Nicolas, Andre, additional, Meseure, Didier, additional, Bellini, Angela, additional, Marabelle, Aurelien, additional, Geoerger, Birgit, additional, Mechta-Grigoriou, Fatima, additional, Schleiermacher, Gudrun, additional, Menger, Laurie, additional, Delattre, Olivier, additional, and Janoueix-Lerosey, Isabelle, additional

Published
2022
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35. Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility

Author

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

Published
2018
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36. Single-cell transcriptomics reveals shared immunosuppressive landscapes of mouse and human neuroblastoma

Author

Costa, Ana; https://orcid.org/0000-0002-0893-3388, Thirant, Cécile; https://orcid.org/0000-0003-3873-5240, Kramdi, Amira, Pierre-Eugène, Cécile, Louis-Brennetot, Caroline, Blanchard, Orphée, Surdez, Didier, Gruel, Nadege, Lapouble, Eve, Pierron, Gaëlle, Sitbon, Deborah, Brisse, Hervé, Gauthier, Arnaud, Fréneaux, Paul, Bohec, Mylène, Raynal, Virginie, Baulande, Sylvain, Leclere, Renaud, Champenois, Gabriel, Nicolas, Andre, Meseure, Didier, Bellini, Angela, Marabelle, Aurelien; https://orcid.org/0000-0002-5816-3019, Geoerger, Birgit, Mechta-Grigoriou, Fatima, Schleiermacher, Gudrun, Menger, Laurie, Delattre, Olivier, Janoueix-Lerosey, Isabelle; https://orcid.org/0000-0003-0434-3003, Costa, Ana; https://orcid.org/0000-0002-0893-3388, Thirant, Cécile; https://orcid.org/0000-0003-3873-5240, Kramdi, Amira, Pierre-Eugène, Cécile, Louis-Brennetot, Caroline, Blanchard, Orphée, Surdez, Didier, Gruel, Nadege, Lapouble, Eve, Pierron, Gaëlle, Sitbon, Deborah, Brisse, Hervé, Gauthier, Arnaud, Fréneaux, Paul, Bohec, Mylène, Raynal, Virginie, Baulande, Sylvain, Leclere, Renaud, Champenois, Gabriel, Nicolas, Andre, Meseure, Didier, Bellini, Angela, Marabelle, Aurelien; https://orcid.org/0000-0002-5816-3019, Geoerger, Birgit, Mechta-Grigoriou, Fatima, Schleiermacher, Gudrun, Menger, Laurie, Delattre, Olivier, and Janoueix-Lerosey, Isabelle; https://orcid.org/0000-0003-0434-3003

Abstract

BACKGROUND High-risk neuroblastoma is a pediatric cancer with still a dismal prognosis, despite multimodal and intensive therapies. Tumor microenvironment represents a key component of the tumor ecosystem the complexity of which has to be accurately understood to define selective targeting opportunities, including immune-based therapies. METHODS We combined various approaches including single-cell transcriptomics to dissect the tumor microenvironment of both a transgenic mouse neuroblastoma model and a cohort of 10 biopsies from neuroblastoma patients, either at diagnosis or at relapse. Features of related cells were validated by multicolor flow cytometry and functional assays. RESULTS We show that the immune microenvironment of MYCN-driven mouse neuroblastoma is characterized by a low content of T cells, several phenotypes of macrophages and a population of cells expressing signatures of myeloid-derived suppressor cells (MDSCs) that are molecularly distinct from the various macrophage subsets. We document two cancer-associated fibroblasts (CAFs) subsets, one of which corresponding to CAF-S1, known to have immunosuppressive functions. Our data unravel a complex content in myeloid cells in patient tumors and further document a striking correspondence of the microenvironment populations between both mouse and human tumors. We show that mouse intratumor T cells exhibit increased expression of inhibitory receptors at the protein level. Consistently, T cells from patients are characterized by features of exhaustion, expressing inhibitory receptors and showing low expression of effector cytokines. We further functionally demonstrate that MDSCs isolated from mouse neuroblastoma have immunosuppressive properties, impairing the proliferation of T lymphocytes. CONCLUSIONS Our study demonstrates that neuroblastoma tumors have an immunocompromised microenvironment characterized by dysfunctional T cells and accumulation of immunosuppressive cells. Our work provides a new and pre

Published
2022

37. Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite

Author

Grünewald, Thomas G P, Bernard, Virginie, Gilardi-Hebenstreit, Pascale, Raynal, Virginie, Surdez, Didier, Aynaud, Marie-Ming, Mirabeau, Olivier, Cidre-Aranaz, Florencia, Tirode, Franck, Zaidi, Sakina, Perot, Gaëlle, Jonker, Anneliene H, Lucchesi, Carlo, Le Deley, Marie-Cécile, Oberlin, Odile, Marec-Bérard, Perrine, Véron, Amélie S, Reynaud, Stephanie, Lapouble, Eve, Boeva, Valentina, Frio, Thomas Rio, Alonso, Javier, Bhatia, Smita, Pierron, Gaëlle, Cancel-Tassin, Geraldine, Cussenot, Olivier, Cox, David G, Morton, Lindsay M, Machiela, Mitchell J, Chanock, Stephen J, Charnay, Patrick, and Delattre, Olivier

Published
2015
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38. Staging of Newly Diagnosed Ewing Sarcoma: Results of Bone Marrow Aspiration and Biopsy Versus (18) FDG-PET/CT Scan for Bone Marrow Involvement

Author

Guinot, Aurélie, primary, Tabone-Eglinger, séverine, additional, Isnardi, Vanina, additional, Bahri, Haifa, additional, Surdez, Didier, additional, delattre, olivier, additional, Pierron, Gaelle, additional, Villemeur, Marie, additional, Lapouble, Eve, additional, Brahmi, Mehdi, additional, Bouhamama, Amine, additional, Corradini, Nadege, additional, and Marec-Bérard, Perrine, additional

Published
2022
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39. Segmental Chromosomal Aberrations in Localized Neuroblastoma Can be Detected in Formalin-Fixed Paraffin-Embedded Tissue Samples and Are Associated With Recurrence

Author

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

Published
2016
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40. Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)

Author

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

Published
2021
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41. Frequency and prognostic impact of alk amplifications and mutations in the european neuroblastoma study group (siopen) high-risk neuroblastoma trial (hr-nbl1)

Author

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

Abstract

PURPOSE In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact. MATERIALS AND METHODS Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n 5 330), ALK mutational profile (n 5 191), or both (n 5 571). RESULTS Genomic ALK amplification (ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n 5 41] 28% [95% CI, 15 to 42]; no-ALKa [n 5 860] 51% [95% CI, 47 to 54], [P , .001]), particularly in cases with metastatic disease. ALK mutations (ALKm) were detected at a clonal level (. 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of ALKm and MNA (P , .001). Among 571 cases with known ALKa and ALKm status, a statistically significant difference in OS was observed between cases with ALKa or clonal ALKm versus subclonal ALKm or no ALK alterations (5-year OS: ALKa [n 5 19], 26% [95% CI, 10 to 47], clonal ALKm[n565] 33% [95% CI, 21 to 44], subclonal ALKm(n522) 48% [95% CI, 26 to 67], and no alteration [n 5 465], 51% [95% CI, 46 to 55], respectively; P 5 .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P , .001), ALKa (HR, 2.38; P 5 .004), and clonal ALKm (HR, 1.77; P 5 .001) were independent predictors of poor outcome. CONCLUSION Genetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integr

Published
2021

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

Author

Peneder, Peter; https://orcid.org/0000-0002-3561-4489, Stütz, Adrian M, Surdez, Didier; https://orcid.org/0000-0002-7118-7859, Krumbholz, Manuela; https://orcid.org/0000-0002-4416-0394, Semper, Sabine, Chicard, Mathieu, Sheffield, Nathan C, Pierron, Gaelle; https://orcid.org/0000-0002-2536-7680, Lapouble, Eve; https://orcid.org/0000-0003-3374-3671, Tötzl, Marcus, Ergüner, Bekir; https://orcid.org/0000-0001-5475-0892, Barreca, Daniele; https://orcid.org/0000-0003-3373-9939, Rendeiro, André F; https://orcid.org/0000-0001-9362-5373, Agaimy, Abbas; https://orcid.org/0000-0002-0445-8161, Boztug, Heidrun, Engstler, Gernot, Dworzak, Michael, Bernkopf, Marie, Taschner-Mandl, Sabine; https://orcid.org/0000-0002-1439-5301, Ambros, Inge M, Myklebost, Ola; https://orcid.org/0000-0002-2866-3223, Marec-Bérard, Perrine, Burchill, Susan Ann, Brennan, Bernadette, Strauss, Sandra J, Whelan, Jeremy, Schleiermacher, Gudrun; https://orcid.org/0000-0002-0133-5879, Schaefer, Christiane, Dirksen, Uta; https://orcid.org/0000-0002-5435-7860, Hutter, Caroline, et al, Peneder, Peter; https://orcid.org/0000-0002-3561-4489, Stütz, Adrian M, Surdez, Didier; https://orcid.org/0000-0002-7118-7859, Krumbholz, Manuela; https://orcid.org/0000-0002-4416-0394, Semper, Sabine, Chicard, Mathieu, Sheffield, Nathan C, Pierron, Gaelle; https://orcid.org/0000-0002-2536-7680, Lapouble, Eve; https://orcid.org/0000-0003-3374-3671, Tötzl, Marcus, Ergüner, Bekir; https://orcid.org/0000-0001-5475-0892, Barreca, Daniele; https://orcid.org/0000-0003-3373-9939, Rendeiro, André F; https://orcid.org/0000-0001-9362-5373, Agaimy, Abbas; https://orcid.org/0000-0002-0445-8161, Boztug, Heidrun, Engstler, Gernot, Dworzak, Michael, Bernkopf, Marie, Taschner-Mandl, Sabine; https://orcid.org/0000-0002-1439-5301, Ambros, Inge M, Myklebost, Ola; https://orcid.org/0000-0002-2866-3223, Marec-Bérard, Perrine, Burchill, Susan Ann, Brennan, Bernadette, Strauss, Sandra J, Whelan, Jeremy, Schleiermacher, Gudrun; https://orcid.org/0000-0002-0133-5879, Schaefer, Christiane, Dirksen, Uta; https://orcid.org/0000-0002-5435-7860, Hutter, Caroline, and et al

Abstract

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.

Published
2021

43. QuantumClone: clonal assessment of functional mutations in cancer based on a genotype-aware method for clonal reconstruction

Author

Deveau, Paul, Colmet Daage, Leo, Oldridge, Derek, Bernard, Virginie, Bellini, Angela, Chicard, Mathieu, Clement, Nathalie, Lapouble, Eve, Combaret, Valerie, Boland, Anne, Meyer, Vincent, Deleuze, Jean-Francois, Janoueix-Lerosey, Isabelle, Barillot, Emmanuel, Delattre, Olivier, Maris, John M, Schleiermacher, Gudrun, and Boeva, Valentina

Subjects
DNA Copy Number Variations, Whole Genome Sequencing, DNA Mutational Analysis, High-Throughput Nucleotide Sequencing, Genome Analysis, Original Papers, Clonal Evolution, Molecular Typing, Gene Frequency, Neoplasms, Mutation, Cluster Analysis, Humans, Software
Abstract

Motivation In cancer, clonal evolution is assessed based on information coming from single nucleotide variants and copy number alterations. Nonetheless, existing methods often fail to accurately combine information from both sources to truthfully reconstruct clonal populations in a given tumor sample or in a set of tumor samples coming from the same patient. Moreover, previously published methods detect clones from a single set of variants. As a result, compromises have to be done between stringent variant filtering [reducing dispersion in variant allele frequency estimates (VAFs)] and using all biologically relevant variants. Results We present a framework for defining cancer clones using most reliable variants of high depth of coverage and assigning functional mutations to the detected clones. The key element of our framework is QuantumClone, a method for variant clustering into clones based on VAFs, genotypes of corresponding regions and information about tumor purity. We validated QuantumClone and our framework on simulated data. We then applied our framework to whole genome sequencing data for 19 neuroblastoma trios each including constitutional, diagnosis and relapse samples. We confirmed an enrichment of damaging variants within such pathways as MAPK (mitogen-activated protein kinases), neuritogenesis, epithelial-mesenchymal transition, cell survival and DNA repair. Most pathways had more damaging variants in the expanding clones compared to shrinking ones, which can be explained by the increased total number of variants between these two populations. Functional mutational rate varied for ancestral clones and clones shrinking or expanding upon treatment, suggesting changes in clone selection mechanisms at different time points of tumor evolution. Availability and implementation Source code and binaries of the QuantumClone R package are freely available for download at https://CRAN.R-project.org/package=QuantumClone. Contact gudrun.schleiermacher@curie.fr or valentina.boeva@inserm.fr Supplementary information Supplementary data are available at Bioinformatics online.

Published
2018

44. Interplay between intrinsic reprogramming potential and microenvironment controls neuroblastoma cell plasticity and identity

Author

Thirant, Cécile, primary, Peltier, Agathe, additional, Durand, Simon, additional, Kramdi, Amira, additional, Louis-Brennetot, Caroline, additional, Pierre-Eugène, Cécile, additional, Costa, Ana, additional, Grelier, Amandine, additional, Zaïdi, Sakina, additional, Gruel, Nadège, additional, Jimenez, Irène, additional, Lapouble, Eve, additional, Pierron, Gaëlle, additional, Brisse, Hervé J., additional, Gauthier, Arnaud, additional, Fréneaux, Paul, additional, Grossetête-Lalami, Sandrine, additional, Baudrin, Laura G., additional, Raynal, Virginie, additional, Baulande, Sylvain, additional, Bellini, Angela, additional, Bhalshankar, Jaydutt, additional, Carcaboso, Angel M., additional, Geoerger, Birgit, additional, Rohrer, Hermann, additional, Surdez, Didier, additional, Boeva, Valentina, additional, Schleiermacher, Gudrun, additional, Delattre, Olivier, additional, and Janoueix-Lerosey, Isabelle, additional

Published
2021
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45. Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma

Author

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

Published
2020
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46. Genetic alterations of ALK in high-risk neuroblastoma patients. A SIOPEN study

Author

Bellini, Angela, Bernard, Virginie, Ambros, Inge, Ambros, Peter F., de Preter, Katleen, Combaret, Valérie, Beiske, Klaus, Jeison, Marta, Marques, Barbara, Morini, Martina, Mazzocco, Katia, Defferrari, Raffaella, Betts, David, Martinsson, Tommy, Mühlethaler-Mottet, Annick, Noguera, Rosa, Font de Mora, Jaime, Vicha, Ales, Ladenstein, Ruth, Valteau-Couanet, Dominique, Rossing, Caroline Maria, Bown, Nick, Tweddle, Deborah, Avigad, Smadar, Lapouble, Eve, Chicard, Mathieu, Leprovost, Nada, Clement, Nathalie, Baulande, Sylvain, Pierron, Gaelle, Irene, Jimenez, Jaydutt, Bhalshankar, Delattre, Olivier, Michon, Jean, and Schleiermacher, Gudrun

Subjects
Neuroblastoma, Tumor Genomics, ALK, hemic and lymphatic diseases, SIOPEN, Doenças Genéticas
Abstract

Background: In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through genomic amplification or activating point mutations. We studied ALK genetic alterations in high-risk NB patients to determine their frequency and prognostic impact. Methods: Diagnostic NB samples from 1039 patients enrolled in the SIOPEN-HR-NBL1 trial were studied to determine the ALK amplification status (copy number analysis; n=337), the ALK mutational profile (Sanger and/or NGS including deep sequencing, n=203) or both (n=499). The sensitivity of ALK mutated/ALK amplified or ALK wildtype NB cell lines ((CLB-GA (R1275Q), CLB-GE (F1174V; ALK-A), SKNBE-2C (ALK wt)) to simultaneous or consecutive combinations of ALK TKIs (crizotinib/lorlatinib) and/or chemotherapy (Etoposide and Doxorubicin) was then tested. Results: Genomic ALK amplifications were detected in 4.4% of cases (37/836); all but 2 showed MYCN amplification. ALK mutations were detected at a clonal level (>20% mutated allele fraction, MAF) in 9.8% of cases (69/702) (F1174 n=25, R1275 n=32, both F1174 and R1275 n=1, F1245 n=6, others n=5) and at a subclonal level (MAF 0.5-20%) in 3.7% of patients (22/586) (F1174 n=11, R1275 n=6, both F1174 and R1275 or F1174 and F1245 n=3, other n=2). A significantly poorer OS and EFS was observed in cases with clonal ALK mutations, versus all others (3-years OS 47% +/-6.4% versus 65% +/-2%, logrank, p< 0.0001) and in those with ALK amplifications, versus all others (3-years OS 31% +/-8.5% versus 66% +/- 1.9%; logrank, p18 months were not retained. The consecutive treatment of Doxorubicin followed by Lorlatinib had a synergistic effect in ALK mutated/amplified NB cell lines. Conclusion: Genetic alterations of ALK (clonal mutations, amplifications) in high-risk NB patients are associated with poorer survival. Further preclinical data are required to determine optimal treatment modalities for integration of TKI in upfront treatment strategies of HR NB patients with ALK alterations. N/A

Published
2019

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

Author

Bellini, Angela, Pötschger, Ulrike, Bernard, Virginie, Lapouble, Eve, Baulande, Sylvain, Ambros, Peter F, Auger, Nathalie, Beiske, Klaus, Bernkopf, Marie, Betts, David R, Bhalshankar, Jaydutt, Bown, Nick, de Preter, Katleen, Clément, Nathalie, Combaret, Valérie, Font de Mora, Jaime, George, Sally L, Jiménez, Irene, Jeison, Marta, and Marques, Barbara

Published
2021
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49. Multiple new susceptibility loci identified in genome-wide association study of Ewing sarcoma

Author

Machiela, Mitchell J., Grünewald, Thomas, Surdez, Didier, Reynaud, Stephanie, Mirabeau, Olivier, Karlins, Eric, Rubio, Rebeca Alba, Zaidi, Sakina, Grossetete-Lalami, Sandrine, Ballet, Stelly, Lapouble, Eve, Laurence, Valérie, Michon, Jean, Pierron, Gaelle, Kovar, Heinrich, Gaspar, Nathalie, Kontny, Udo, González-Neira, Anna, Picci, Piero, Alonso, Javier, Patino-Garcia, Ana, Corradini, Nadège, Freedman, Neal D., Rothman, Nathaniel, Dagnall, Casey L., Burdette, Laurie, Jones, Kristine, Manning, Michelle, Wyatt, Kathleen, Zhou, Weiyin, Yeager, Meredith, Cox, David G., Hoover, Robert N., Khan, Javed, Armstrong, Gregory T., Leisenring, Wendy M., Bhatia, Smita, Robison, Leslie L., Dirksen, Uta, Metzler, Markus, Hartmann, Wolfgang, Strauch, Konstantin, Kirchner, Thomas, Kulozik, Andreas E., Morton, Lindsay M., Mirabello, Lisa, Tucker, Margaret A., Tirode, Franck, Chanock, Stephen J., and Delattre, Olivier

Subjects
Medizin
Published
2018

50. Exosomes transmit retroelement RNAs to drive inflammation and immunosuppression in Ewing Sarcoma

Author

Evdokimova, Valentina, primary, Ruzanov, Peter, additional, Gassmann, Hendrik, additional, Zaidi, Syed H., additional, Peltekova, Vanya, additional, Heisler, Lawrence E., additional, McPherson, John D., additional, Orlic-Milacic, Marija, additional, Specht, Katja, additional, Steiger, Katja, additional, Schober, Sebastian J., additional, Thiel, Uwe, additional, McKee, Trevor D., additional, Zaidi, Mark, additional, Spring, Christopher M., additional, Lapouble, Eve, additional, Delattre, Olivier, additional, Burdach, Stefan, additional, Stein, Lincoln D., additional, and Sorensen, Poul H., additional

Published
2019
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