title: The survival gene MED4 explains low penetrance retinoblastoma in patients with large RB1 deletion.
abstract: Retinoblastoma is a non-hereditary as well as an inherited pediatric tumor of the developing retina resulting from the inactivation of both copies of the RB1 tumor suppressor gene. Familial retinoblastoma is a highly penetrant genetic disease that usually develops by carrying germline mutations that inactivate one allele of the RB1 gene, leading to multiple retinoblastomas. However, large and complete germline RB1 deletions are associated with low or no tumor risk for reasons that remain unknown. In this study, we define a minimal genomic region associated with this low penetrance. This region encompasses few genes including MED4 a subunit of the mediator complex. We further show that retinoblastoma RB1 -/- cells cannot survive in the absence of MED4, both in vitro and in orthotopic xenograft models in vivo, therefore identifying MED4 as a survival gene in retinoblastoma. We propose that the contiguous loss of the adjacent retinoblastoma gene, MED4, explains the low penetrance in patients with large deletions that include both RB1 and MED4. Our findings also point to another synthetic lethal target in tumors with inactivated RB1 and highlight the importance of collateral damage in carcinogenesis.
authors.affiliation: Service de Génétique, Institut Curie, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Dehainault
authors.affiliation: Institut Curie, Section Recherche, Orsay, France CNRS UMR3347 INSERM U1021 Université Paris Sud and.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Garancher
authors.affiliation: Service de Génétique, Institut Curie, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Castéra
authors.affiliation: Département d'oncologie chirurgicale, service d'Ophtalmologie, Institut Curie, Paris, France Laboratoire d'Investigation Préclinique, Institut Curie, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cassoux
authors.affiliation: Département d'oncologie pédiatrique, adolescents jeunes adultes and.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Aerts
authors.affiliation: Département d'oncologie pédiatrique, adolescents jeunes adultes and Université Paris Descartes, Sciences pharmaceutiques et biologiques, Sorbonne Paris Cité, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Doz
authors.affiliation: Département d'oncologie chirurgicale, service d'Ophtalmologie, Institut Curie, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Desjardins
authors.affiliation: Département d'oncologie chirurgicale, service d'Ophtalmologie, Institut Curie, Paris, France.
authors.forename: Livia
authors.initials: L
authors.lastname: Lumbroso
authors.affiliation: Institut Curie, CNRS UMR 3664, Paris, France.
authors.forename: Rocío
authors.initials: R
authors.lastname: Montes de Oca
authors.affiliation: Institut Curie, CNRS UMR 3664, Paris, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Almouzni
authors.affiliation: Service de Génétique, Institut Curie, Paris, France INSERM U830, centre de recherche de l'Institut Curie, Paris, France Université Paris Descartes, Sciences pharmaceutiques et biologiques, Sorbonne Paris Cité, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.affiliation: Institut Curie, Section Recherche, Orsay, France CNRS UMR3347 INSERM U1021 Université Paris Sud and claude.houdayer@curie.fr celio.pouponnot@curie.fr.
authors.forename: Celio
authors.initials: C
authors.lastname: Pouponnot
authors.affiliation: Service de Génétique, Institut Curie, Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Gauthier-Villars
authors.affiliation: Service de Génétique, Institut Curie, Paris, France INSERM U830, centre de recherche de l'Institut Curie, Paris, France Université Paris Descartes, Sciences pharmaceutiques et biologiques, Sorbonne Paris Cité, Paris, France claude.houdayer@curie.fr celio.pouponnot@curie.fr.
authors.forename: Claude
authors.initials: C
authors.lastname: Houdayer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D055028:Comparative Genomic Hybridization; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D055786:Gene Knockout Techniques; D064593:Heterografts; D006801:Humans; D008297:Male; D056892:Mediator Complex / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010375:Pedigree; D019683:Penetrance; D034622:RNA Interference; D012175:Retinoblastoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016160:Retinoblastoma Protein / Q000235:genetics*; D014410:Tumor Stem Cell Assay
chemical_list: C491863:MED4 protein, human; D056892:Mediator Complex; D016160:Retinoblastoma Protein