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

• DOI: 10.1038/s41467-021-25792-0
• Publication Date: 2021-09-22T10:03:10Z
• Authors: 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-O...; 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...; Alexandre Matet; Laurence Desjardins; Guillem Pascual-P...; Mariona Suñol; Jaume Catala-Mora; Genoveva Correa L...; Jérôme Couturier; Emmanuel Barillot; Paula Schaiquevich; Marion Gauthier-V...; Dominique Stoppa-...; Lisa Golmard; Claude Houdayer; Hervé Brisse; Isabelle Bernard-...; Eric Letouzé; Alain Viari; Simon Saule; Xavier Sastre-Garau; François Doz; Angel M. Carcaboso; Nathalie Cassoux; Celio Pouponnot; Olivier Goureau; Guillermo Chantada; Aurélien de Reyniès; Isabelle Aerts; François Radvanyi
• Keywords: Retinoblastoma; Retinoblastoma protein

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