A high-risk retinoblastoma subtype with stemness features, dedifferentiated cone states and neuronal/ganglion cell gene expression

Jing Liu, Daniela Ottaviani, Meriem Sefta, Céline Desbrousses, Elodie Chapeaublanc, Rosario Aschero, Nanor Sirab, Fabiana Lubieniecki, Gabriela Lamas, Laurie Tonon, Catherine Dehainault, Clément Hua, Paul Fréneaux, Sacha Reichman, Narjesse Karboul, Anne Biton, Liliana Mirabal-Ortega, Magalie Larcher, Céline Brulard, Sandrine Arrufat, André Nicolas, Nabila Elarouci, Tatiana Popova, Fariba Némati, Didier Decaudin, David Gentien, Sylvain Baulande, Odette Mariani, Florent Dufour, Sylvain Guibert, Céline Vallot, Livia Lumbroso-Le Rouic, Alexandre Matet, Laurence Desjardins, Guillem Pascual-Pasto, Mariona Suñol, Jaume Catala-Mora, Genoveva Correa Llano, Jérôme Couturier, Emmanuel Barillot, Paula Schaiquevich, Marion Gauthier-Villars, Dominique Stoppa-Lyonnet, Lisa Golmard, Claude Houdayer, Hervé Brisse, Isabelle Bernard-Pierrot, Eric Letouzé, Alain Viari, Simon Saule, Xavier Sastre-Garau, François Doz, Angel M. Carcaboso, Nathalie Cassoux, Celio Pouponnot, Olivier Goureau, Guillermo Chantada, Aurélien Reyniès, Isabelle Aerts and François Radvanyi ()
Additional contact information
Jing Liu: Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University
Daniela Ottaviani: Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University
Meriem Sefta: Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University
Céline Desbrousses: Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University
Elodie Chapeaublanc: Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University
Rosario Aschero: Pathology Service, Hospital J.P. Garrahan
Nanor Sirab: Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University
Fabiana Lubieniecki: Pathology Service, Hospital J.P. Garrahan
Gabriela Lamas: Pathology Service, Hospital J.P. Garrahan
Laurie Tonon: Centre Léon Bérard
Catherine Dehainault: Département de Biologie des Tumeurs, Institut Curie
Clément Hua: Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University
Paul Fréneaux: Département de Biologie des Tumeurs, Institut Curie
Sacha Reichman: Institut de la Vision, Sorbonne Université, INSERM, CNRS
Narjesse Karboul: Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University
Anne Biton: Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University
Liliana Mirabal-Ortega: Institut Curie, CNRS, UMR3347, PSL Research University
Magalie Larcher: Institut Curie, CNRS, UMR3347, PSL Research University
Céline Brulard: Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University
Sandrine Arrufat: Département de Biologie des Tumeurs, Institut Curie
André Nicolas: Département de Biologie des Tumeurs, Institut Curie
Nabila Elarouci: Ligue Nationale Contre le Cancer
Tatiana Popova: Institut Curie, PSL Research University
Fariba Némati: Département de Recherche Translationnelle, Institut Curie
Didier Decaudin: Département de Recherche Translationnelle, Institut Curie
David Gentien: Département de Recherche Translationnelle, Institut Curie
Sylvain Baulande: Institut Curie, PSL Research University, NGS Platform
Odette Mariani: Département de Biologie des Tumeurs, Institut Curie
Florent Dufour: Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University
Sylvain Guibert: GeCo Genomics Consulting, Integragen
Céline Vallot: GeCo Genomics Consulting, Integragen
Livia Lumbroso-Le Rouic: Département de Chirurgie, Service d’Ophtalmologie, Institut Curie
Alexandre Matet: Département de Chirurgie, Service d’Ophtalmologie, Institut Curie
Laurence Desjardins: Département de Chirurgie, Service d’Ophtalmologie, Institut Curie
Guillem Pascual-Pasto: Institut de Recerca Sant Joan de Déu
Mariona Suñol: Institut de Recerca Sant Joan de Déu
Jaume Catala-Mora: Institut de Recerca Sant Joan de Déu
Genoveva Correa Llano: Institut de Recerca Sant Joan de Déu
Jérôme Couturier: Département de Biologie des Tumeurs, Institut Curie
Emmanuel Barillot: Institut Curie, PSL Research University
Paula Schaiquevich: Pathology Service, Hospital J.P. Garrahan
Marion Gauthier-Villars: Département de Biologie des Tumeurs, Institut Curie
Dominique Stoppa-Lyonnet: Département de Biologie des Tumeurs, Institut Curie
Lisa Golmard: Département de Biologie des Tumeurs, Institut Curie
Claude Houdayer: Département de Biologie des Tumeurs, Institut Curie
Hervé Brisse: Institut Curie
Isabelle Bernard-Pierrot: Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University
Eric Letouzé: Sorbonne Universités, INSERM
Alain Viari: Centre Léon Bérard
Simon Saule: Institut Curie, CNRS, UMR3347, PSL Research University
Xavier Sastre-Garau: Département de Biologie des Tumeurs, Institut Curie
François Doz: Université de Paris
Angel M. Carcaboso: Institut de Recerca Sant Joan de Déu
Nathalie Cassoux: Département de Chirurgie, Service d’Ophtalmologie, Institut Curie
Celio Pouponnot: Institut Curie, CNRS, UMR3347, PSL Research University
Olivier Goureau: Institut de la Vision, Sorbonne Université, INSERM, CNRS
Guillermo Chantada: Precision Medicine, Hospital J.P. Garrahan
Aurélien Reyniès: Ligue Nationale Contre le Cancer
Isabelle Aerts: Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University
François Radvanyi: Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract Retinoblastoma is the most frequent intraocular malignancy in children, originating from a maturing cone precursor in the developing retina. Little is known on the molecular basis underlying the biological and clinical behavior of this cancer. Here, using multi-omics data, we demonstrate the existence of two retinoblastoma subtypes. Subtype 1, of earlier onset, includes most of the heritable forms. It harbors few genetic alterations other than the initiating RB1 inactivation and corresponds to differentiated tumors expressing mature cone markers. By contrast, subtype 2 tumors harbor frequent recurrent genetic alterations including MYCN-amplification. They express markers of less differentiated cone together with neuronal/ganglion cell markers with marked inter- and intra-tumor heterogeneity. The cone dedifferentiation in subtype 2 is associated with stemness features including low immune and interferon response, E2F and MYC/MYCN activation and a higher propensity for metastasis. The recognition of these two subtypes, one maintaining a cone-differentiated state, and the other, more aggressive, associated with cone dedifferentiation and expression of neuronal markers, opens up important biological and clinical perspectives for retinoblastomas.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25792-0

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DOI: 10.1038/s41467-021-25792-0

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