Abstract
PURPOSE: It is well known that individuals with hereditary retinoblastoma are at lifelong high risk for developing subsequent malignant neoplasms (SMN). However, the role that non-RB1 germline variants play in tumorigenesis and SMN risk has not yet been studied. The purpose of this study is to report the frequency and spectrum of non-RB1 germline cancer predisposing variants in individuals with retinoblastoma (RB). METHODS: Retrospective data collection from institutional electronic medical records of 94 individuals seen at our institution with personal history of retinoblastoma, who had undergone next-generation sequencing germline analysis. RESULTS: The prevalence of individuals with cancer predisposition was 57% (54/94). Of these individuals, 76% (41/54) had a pathogenic/likely pathogenic (P/LP) variant only in the RB1 gene, 9% (5/54) harbored a P/LP variant only in a non-RB1 gene, and 11% (6/54) had both. No difference was found between patients with and without non-RB1 variants when comparing demographic and clinical characteristics, including time to SMN. Variants were found in 7 different genes, with only 1 variant repeating 3 times. CONCLUSION: In this small cohort of patients with retinoblastoma, non-RB1 variants did not appear to augment tumorigenesis or disease progression. Larger studies are required to determine associations between specific variants and development of SMN.