title: Genotype-phenotype correlation in the presentation of retinoblastoma among 149 patients.
abstract: In this work, we describe the association between a germline RB1 mutation and disease presentation characteristics of retinoblastoma. The study evaluates a retrospective cohort of 164 of the 295 patients with retinoblastoma who were treated at a single center between 1988 and 2013 and who were referred for genetic evaluation. Peripheral blood was evaluated for RB1 mutations via Multiplex Ligation-dependent Probe Amplification (MLPA), sequencing, and detection of recurrent CpG transition mutations. Patients with an RB1 mutation were compared to patients without a mutation, regarding epidemiological factors and clinical presentation. Genetic analysis was completed for 149 patients. An RB1 mutation was identified in 76 children (51.0%) including 90.0% of the bilateral patients, and 19.8% of the unilateral unifocal patients (24.7% if we include the unilateral multifocal cases). The most common mutations were a stop codon (38.2%), a splicing error (19.7%) and a large deletion (15.8%). The mutation type correlated only with sex (Likelihood ratio, p = 0.0240) and with macular involvement (Likelihood ratio, p = 0.0591 and Fisher's exact one tail test p = 0.0459 for more macular involvement if there are germline mutations). It did not correlate with laterality, with the reason for referral, or with diagnosis age. However, identification of a mutation was more common in babies diagnosed under one year of age (Likelihood ratio, p < 0.0001). In conclusion, we were surprised that our genetic tests have also found mutations in 24.7% of patients with unilateral retinoblastoma in addition to most of the bilateral children. These unilateral patients with a germline mutation have an increased risk for other cancers throughout their lives, and their first-degree relatives have an increased risk for retinoblastoma. Therefore, genetic testing for RB1 mutation should be offered to all patients, including the unilateral cases.
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Electronic address: shahar.frenkel@gmail.com.
authors.forename: Shahar
authors.initials: S
authors.lastname: Frenkel
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ofira
authors.initials: O
authors.lastname: Zloto
authors.affiliation: Departments of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Sagi
authors.affiliation: Departments of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Avishag
authors.initials: A
authors.lastname: Fraenkel
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Jacob
authors.initials: J
authors.lastname: Pe'er
mesh_terms: D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D016161:Genes, Retinoblastoma / Q000235:genetics; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008266:Macula Lutea / Q000473:pathology; D008297:Male; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation; D012044:Regression Analysis; D019572:Retinal Neoplasms / Q000235:genetics* / Q000473:pathology; D012175:Retinoblastoma / Q000235:genetics* / Q000473:pathology; D016160:Retinoblastoma Protein / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D016160:Retinoblastoma Protein
keywords: Genetic counseling; Genotype-phenotype; Germline mutations; RB1; Retinoblastoma