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Subset of retinoblastoma tumours is associated with BRCA1/2 mutations
  1. Yong Joon Kim1,
  2. Hyo Song Park2,3,
  3. Jeonghwan Youk4,
  4. Jung Woo Han5,
  5. Suk Ho Byeon1,
  6. Sung Soo Kim1,
  7. Young Seok Ju6,7,
  8. Christopher Seungkyu Lee1
  1. 1 Department of Ophthalmology, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Republic of Korea
  2. 2 Department of Ophthalmology, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea
  3. 3 Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, Bucheon, Republic of Korea
  4. 4 Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
  5. 5 Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
  6. 6 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
  7. 7 GENOME INSIGHT Inc, San Diego, CA 92121, USA
  1. Correspondence to Dr Christopher Seungkyu Lee, Department of Ophthalmology, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Republic of Korea; sklee219{at}yuhs.ac

Abstract

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.

  • Genetics
  • Retina

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Footnotes

  • 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.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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