PMID- 32556071 OWN - NLM STAT- MEDLINE DCOM- 20210122 LR - 20210619 IS - 2168-6173 (Electronic) IS - 2168-6165 (Print) IS - 2168-6165 (Linking) VI - 138 IP - 8 DP - 2020 Aug 1 TI - Association Between Genotype and Phenotype in Consecutive Unrelated Individuals With Retinoblastoma. PG - 843-850 LID - 10.1001/jamaophthalmol.2020.2100 [doi] AB - IMPORTANCE: Retinoblastoma (RB) is the most common pediatric intraocular neoplasm. RB is a complex model in which atypical pathogenic variants, modifier genes, imprinting, and mosaicism are known to be associated with the phenotype. In-depth understanding of RB therefore requires large genotype-phenotype studies. OBJECTIVE: To assess the association between genotype and phenotype in patients with RB. DESIGN, SETTING, AND PARTICIPANTS: This single-center, retrospective cohort study, conducted from January 1, 2000, to September 30, 2017, enrolled 1404 consecutive ascertained patients with RB who consulted an oncogeneticist. All patients had their genotype and phenotype recorded. Statistical analysis was performed from July 1, 2018, to December 31, 2018. MAIN OUTCOMES AND MEASURES: RB1 germline and somatic pathogenic variant types, family history, and disease presentation characteristics (ie, age at diagnosis, sex, laterality, and International Intraocular Retinoblastoma Classification group). RESULTS: Among 1404 patients with RB (734 [52.3%] female; mean [SD] age, 20.2 [21.2] months), 866 cases (61.7%) were unilateral and 538 cases (38.3%) were bilateral. Loss of function variants were found throughout the coding sequence, with 259 of 272 (95.2%) somatic pathogenic variants and 537 of 606 (88.6%) germline pathogenic variants (difference, 6.6%; 95% CI, 4.0%-9.2%; P < .001) after excluding tumor-specific pathogenic variants (ie, promoter methylation and loss of heterozygosity); a novel low-penetrance region was identified in exon 24. Compared with germline pathogenic variants estimated to retain RB protein expression, germline pathogenic variants estimated to abrogate RB protein expression were associated with an earlier mean (SD) age at diagnosis (12.3 [11.3] months among 457 patients vs 16.3 [13.2] months among 55 patients; difference, 4 months; 95% CI, 1.9-6.1 months; P = .01), more frequent bilateral involvement (84.2% among 452 patients vs 65.2% among 45 patients; difference, 18.9%; 95% CI, 14.5%-23.3%; P < .001), and more advanced International Intraocular Retinoblastoma Classification group (85.3% among 339 patients vs 73.9% among 34 patients; difference: 11.4%; 95% CI, 6.5%-16.3%; P = .047). Among the 765 nongermline carriers of an RB1 pathogenic variant, most were female (419 females [54.8%] vs 346 males [45.2%]; P = .008), and males were more likely to have bilateral RB (23 males [71.4%] vs 12 females [34.3%]; P = .01). CONCLUSIONS AND RELEVANCE: These results suggest that RB risk is associated with the germline pathogenic variant and with maintenance of RB protein and that there is a sex-linked mechanism for nongermline carriers. FAU - Salviat, Flore AU - Salviat F AD - Department of Biostatistics, Institut Curie, PSL Research University, Saint-Cloud, France. FAU - Gauthier-Villars, Marion AU - Gauthier-Villars M AD - Department of Genetics, Institut Curie, PSL Research University, Department of Genetics, Paris, France. FAU - Carton, Matthieu AU - Carton M AD - Department of Biostatistics, Institut Curie, PSL Research University, Saint-Cloud, France. FAU - Cassoux, Nathalie AU - Cassoux N AD - Faculty of Medicine Paris-Descartes, Paris University, Paris, France. AD - Service of Ophthalmology, Department of Surgical Oncology, Institut Curie, Paris, France. FAU - Lumbroso-Le Rouic, Livia AU - Lumbroso-Le Rouic L AD - Service of Ophthalmology, Department of Surgical Oncology, Institut Curie, Paris, France. FAU - Dehainault, Catherine AU - Dehainault C AD - Department of Genetics, Institut Curie, PSL Research University, Department of Genetics, Paris, France. FAU - Levy, Christine AU - Levy C AD - Service of Ophthalmology, Department of Surgical Oncology, Institut Curie, Paris, France. FAU - Golmard, Lisa AU - Golmard L AD - Department of Genetics, Institut Curie, PSL Research University, Department of Genetics, Paris, France. FAU - Aerts, Isabelle AU - Aerts I AD - Oncology Center, Soins, Innovation, Recherche en Oncologie de l'Enfant, l'Adolescent et du Jeune Adulte, Institut Curie, Paris, France. FAU - Doz, Francois AU - Doz F AD - Faculty of Medicine Paris-Descartes, Paris University, Paris, France. AD - Oncology Center, Soins, Innovation, Recherche en Oncologie de l'Enfant, l'Adolescent et du Jeune Adulte, Institut Curie, Paris, France. FAU - Bonnet-Serrano, Fideline AU - Bonnet-Serrano F AD - Department of Genetics, Institut Curie, PSL Research University, Department of Genetics, Paris, France. FAU - Hayek, Stephanie AU - Hayek S AD - Department of Genetics, Institut Curie, PSL Research University, Department of Genetics, Paris, France. FAU - Savignoni, Alexia AU - Savignoni A AD - Department of Biostatistics, Institut Curie, PSL Research University, Saint-Cloud, France. FAU - Stoppa-Lyonnet, Dominique AU - Stoppa-Lyonnet D AD - Department of Genetics, Institut Curie, PSL Research University, Department of Genetics, Paris, France. AD - Faculty of Medicine Paris-Descartes, Paris University, Paris, France. AD - Research Center Institut National de la Sante et de la Recherche Medicale, Unit U830, Institut Curie, Paris, France. FAU - Houdayer, Claude AU - Houdayer C AD - Department of Genetics, Institut Curie, PSL Research University, Department of Genetics, Paris, France. AD - Department of Genetics, Rouen University Hospital, Rouen, France. AD - University of Rouen Normandy, UNIROUEN, Mont-Saint-Aignan, France. AD - Institut National de la Sante et de la Recherche Medicale U1245, Normandy Center for Genomic and Personalized Medicine, Rouen, France. LA - eng PT - Comparative Study PT - Journal Article PL - United States TA - JAMA Ophthalmol JT - JAMA ophthalmology JID - 101589539 RN - 0 (DNA, Neoplasm) RN - 0 (RB1 protein, human) RN - 0 (Retinoblastoma Binding Proteins) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) SB - IM MH - Adolescent MH - Adult MH - Child MH - Child, Preschool MH - DNA, Neoplasm/genetics MH - Female MH - *Genetic Association Studies MH - Genetic Predisposition to Disease MH - Germ-Line Mutation MH - Humans MH - Infant MH - Infant, Newborn MH - Male MH - Penetrance MH - Retinal Neoplasms/*genetics/pathology MH - Retinoblastoma/*genetics/pathology MH - Retinoblastoma Binding Proteins/*genetics MH - Retrospective Studies MH - Ubiquitin-Protein Ligases/*genetics MH - Young Adult PMC - PMC7303903 COIS- Conflict of Interest Disclosures: Dr Doz reported receiving personal fees from Bayer, BMS, Celgene, Loxo Oncology, Roche, and Servier outside the submitted work. Dr Stoppa-Lyonnet reported receiving nonfinancial support from Institut Curie during the conduct of the study. No other disclosures were reported. EDAT- 2020/06/20 06:00 MHDA- 2021/01/23 06:00 PMCR- 2021/06/18 CRDT- 2020/06/20 06:00 PHST- 2020/06/20 06:00 [pubmed] PHST- 2021/01/23 06:00 [medline] PHST- 2020/06/20 06:00 [entrez] PHST- 2021/06/18 00:00 [pmc-release] AID - 2766938 [pii] AID - eoi200043 [pii] AID - 10.1001/jamaophthalmol.2020.2100 [doi] PST - ppublish SO - JAMA Ophthalmol. 2020 Aug 1;138(8):843-850. doi: 10.1001/jamaophthalmol.2020.2100.