Non-RB1 germline cancer predisposing variants found in retinoblastoma patients.

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- 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- 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 gene, 9% (5/54) harbored a P/LP variant only in a non- gene, and 11% (6/54) had both. No difference was found between patients with and without non- 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- variants did not appear to augment tumorigenesis or disease progression. Larger studies are required to determine associations between specific variants and development of SMN.