Subset of retinoblastoma tumours is associated withBRCA1/2mutations

Abstract

BackgroundWe investigated the potential association between pathogenic BRCA1/2 variants and retinoblastoma pathogenicity.MethodsIn this single-centre, retrospective case series, we performed hereditary cancer panel tests using blood samples for patients with retinoblastoma diagnosed between March 2017 and October 2021. Bioinformatics prediction tools were then used to conduct in silico pathogenicity assessments for patients withBRCA1/2family variants, in addition to the American College of Medical Genetics and Genomics (ACMG) variant classification. One patient with a germlineBRCA1variant was analysed with whole-genome sequencing (WGS), mutational signature analysis and methylation analysis forRB1andBRCAusing the patient’s tumour and blood samples.ResultsOf 30 retinoblastoma patients who underwent panel sequencing, six (20%) were found to carry germline variants in the BRCA1/2 or BRIP1 genes. Among these six patients, two had pathogenic or likely pathogenic variants as per the ACMG variant classification. Additionally, three patients showed potential pathogenic BRCA1/2 family variants through further analysis with alternative bioinformatics prediction tools. In the WGS analysis of a tumour from a patient with a germline likely pathogenicBRCA1variant in one allele, we observed the loss of one RB1 allele due to a large deletion. No somatic non-synonymous mutations or frameshift indels were detected in the RB1 locus of the remaining allele. This sample also showedBRCA1gene promoter hypermethylation in the tumour, indicating additional epigenetic silencing.ConclusionThis study demonstrated that some retinoblastoma patients harboured germlineBRCA1/2family variants, which may be associated with the development of retinoblastoma along withRB1mutations.