title: A Parent-of-Origin Effect Impacts the Phenotype in Low Penetrance Retinoblastoma Families Segregating the c.1981C>T/p.Arg661Trp Mutation of RB1.
abstract: Retinoblastoma (Rb), the most common pediatric intraocular neoplasm, results from inactivation of both alleles of the RB1 tumor suppressor gene. The second allele is most commonly lost, as demonstrated by loss of heterozygosity studies. RB1 germline carriers usually develop bilateral tumors, but some Rb families display low penetrance and variable expressivity. In order to decipher the underlying mechanisms, 23 unrelated low penetrance pedigrees segregating the common c.1981C>T/p.Arg661Trp mutation and other low penetrance mutations were studied. In families segregating the c.1981C>T mutation, we demonstrated, for the first time, a correlation between the gender of the transmitting carrier and penetrance, as evidenced by Fisher's exact test: the probability of being unaffected is 90.3% and 32.5% when the mutation is inherited from the mother and the father, respectively (p-value = 7.10(-7). Interestingly, a similar correlation was observed in families segregating other low penetrance alleles. Consequently, we investigated the putative involvement of an imprinted, modifier gene in low penetrance Rb. We first ruled out a MED4-driven mechanism by MED4 methylation and expression analyses. We then focused on the differentially methylated CpG85 island located in intron 2 of RB1 and showing parent-of-origin-specific DNA methylation. This differential methylation promotes expression of the maternal c.1981C>T allele. We propose that the maternally inherited c.1981C>T/p.Arg661Trp allele retains sufficient tumor suppressor activity to prevent retinoblastoma development. In contrast, when the mutation is paternally transmitted, the low residual activity would mimic a null mutation and subsequently lead to retinoblastoma. This implies that the c.1981C>T mutation is not deleterious per se but needs to be destabilized in order to reach pRb haploinsufficiency and initiate tumorigenesis. We suggest that this phenomenon might be a general mechanism to explain phenotypic differences in low penetrance Rb families.
authors.affiliation: Service de Génétique, Institut Curie, Paris, France.
authors.forename: Philippine
authors.initials: P
authors.lastname: Eloy
authors.affiliation: Service de Génétique, Institut Curie, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Dehainault
authors.affiliation: CNRS UMR144, centre de recherche de l'Institut Curie, Paris, France.
authors.forename: Meriem
authors.initials: M
authors.lastname: Sefta
authors.affiliation: Département d'oncologie pédiatrique, adolescents jeunes adultes, Institut Curie, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Aerts
authors.affiliation: Département d'oncologie pédiatrique, adolescents jeunes adultes, Institut Curie, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Doz
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Département d'oncologie chirurgicale, service d'Ophtalmologie, Institut Curie, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cassoux
authors.affiliation: Département d'oncologie chirurgicale, service d'Ophtalmologie, Institut Curie, Paris, France.
authors.forename: Livia
authors.initials: L
authors.lastname: Lumbroso le Rouic
authors.affiliation: Service de Génétique, Institut Curie, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|INSERM U830, centre de recherche de l'Institut Curie, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.affiliation: CNRS UMR144, centre de recherche de l'Institut Curie, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Radvanyi
authors.affiliation: Institut Curie, PSL Research University, Paris, France.|CNRS UMR 3244, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
authors.forename: Gaël A
authors.initials: GA
authors.lastname: Millot
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.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|INSERM U830, centre de recherche de l'Institut Curie, Paris, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Houdayer
mesh_terms: D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D056892:Mediator Complex / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D019572:Retinal Neoplasms / Q000235:genetics* / Q000473:pathology; D012175:Retinoblastoma / Q000235:genetics* / Q000473:pathology; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C491863:MED4 protein, human; D056892:Mediator Complex; D016160:Retinoblastoma Protein