Background We investigated the potential association between pathogenic BRCA1/2 variants and retinoblastoma pathogenicity.
Methods In 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 with BRCA1/2 family variants, in addition to the American College of Medical Genetics and Genomics (ACMG) variant classification. One patient with a germline BRCA1 variant was analysed with whole-genome sequencing (WGS), mutational signature analysis and methylation analysis for RB1 and BRCA using the patient’s tumour and blood samples.
Results Of 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 pathogenic BRCA1 variant 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 showed BRCA1 gene promoter hypermethylation in the tumour, indicating additional epigenetic silencing.
Conclusion This study demonstrated that some retinoblastoma patients harboured germline BRCA1/2 family variants, which may be associated with the development of retinoblastoma along with RB1 mutations.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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YJK and HSP are joint first authors.
Contributors Conceptualisation, methodology, project administration, writing—review and editing, project administration: YJK and CSL; validation: YJK, HSP and CSL; formal analysis: YJK, HSP, JY and YSJ; investigation: YJK, HSP, JY, and YSJ; resources: YJK, JY, JWH, YSJ, CSL; data curation: YJK, HSP, JY, and YSJ; writing—original draft preparation: YJK, HSP and CSL; supervision: YJK, SHB, SSK, YSJ and CSL. CSL is guarantor.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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