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  • Predicting the likelihood of a BRCA1/2 pathogenic variant being somatic by testing only tumour DNA in non-mucinous high-grade epithelial ovarian cancer

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Original research
Predicting the likelihood of a BRCA1/2 pathogenic variant being somatic by testing only tumour DNA in non-mucinous high-grade epithelial ovarian cancer
  1. Robert D Morgan1,
  2. George J Burghel2,
  3. Nicola Flaum1,2,3,
  4. Michael Bulman2,
  5. Philip Smith2,
  6. Andrew R Clamp1,4,
  7. Jurjees Hasan1,
  8. Claire Mitchell1,
  9. Zena Salih1,
  10. Emma R Woodward2,5,
  11. Fiona Lalloo2,5,
  12. Joseph Shaw6,
  13. Sudha Desai7,
  14. Emma J Crosbie4,8,
  15. Richard J Edmondson4,8,
  16. Helene Schlecht2,
  17. Andrew J Wallace2,
  18. Gordon C Jayson1,4,
  19. D Gareth R Evans2,3,5
  1. 1 Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
  2. 2 North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, UK
  3. 3 Division of Evolution, Infection and Genomics, University of Manchester, Manchester, UK
  4. 4 Division of Cancer Sciences, University of Manchester, Manchester, UK
  5. 5 Department of Clinical Genetics, Manchester University NHS Foundation Trust, Manchester, UK
  6. 6 Department of Histopathology, Manchester University NHS Foundation Trust, Manchester, UK
  7. 7 Department of Histopathology, The Christie NHS Foundation Trust, Manchester, UK
  8. 8 Department of Gynaecological Surgery, Manchester University NHS Foundation Trust, Manchester, UK
  1. Correspondence to Dr Robert D Morgan, Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK; robert.morgan7{at}nhs.net

Abstract

Aims Clinical guidelines recommend testing both germline and tumour DNA for BRCA1/2 pathogenic variants (PVs) in non-mucinous high-grade epithelial ovarian cancer (NMEOC). In this study, we show that some tumour BRCA1/2 PVs are highly likely to be somatic based on certain clinical and variant characteristics, meaning it may not be necessary to test all NMEOC cases for germline BRCA1/2 PVs.

Methods An observational study that included all tumour BRCA1/2 PVs detected in cases of NMEOC in the Northwest of England between July 2017 and February 2022. All tumour BRCA1/2 PVs were compared with PVs recorded in a prospectively gathered pan-cancer germline BRCA1/2 (gBRCA) testing database for the same geographical region (gBRCA1 PVs=910 and gBRCA2 PVs=922). Tumour BRCA1/2 PVs were categorised as common (≥1%), uncommon (<1%) or absent from the germline database.

Results One hundred and thirteen tumour BRCA1/2 PVs were detected in 111 NMEOC cases. There were 69 germline and 44 somatic variants. The mean age at diagnosis for gBRCA and somatic BRCA1/2 (sBRCA) PVs was 56.9 and 68.5 years, respectively (Student's t-test p<0.0001). All sBRCA PVs were detected in non-familial cases. All tumour BRCA1/2 PVs with a variant allele frequency (VAF) <35% in non-familial cases were somatic variants. Eighty-one per cent of germline-tumour BRCA1/2 PVs were present (common=31, uncommon=25) in the gBRCA testing database, while 89% of somatic-tumour BRCA1/2 PVs were absent (n=39).

Conclusions We predict the likelihood of a tumour BRCA1/2 PV being somatic is 99.8% in non-familial cases of NMEOC diagnosed aged ≥75, where the VAF is ≤30% and there is no regional germline commonality.

  • Ovarian Neoplasms
  • GENETICS
  • Biomarkers, Tumor

Data availability statement

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

https://doi.org/10.1136/jcp-2022-208369

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    Data availability statement

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

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    Footnotes

    • Handling editor Runjan Chetty.

    • Contributors RDM and DGRE designed and initiated the study, and are responsible for the overall content as the guarantor. RDM, NF, ARC, JH, CM, ZS, ERW, FL, EJC, RJE, GCJ and DGRE gained consent for germline and tumour BRCA1/2 testing. JS and SD reported the histological subtype of epithelial ovarian cancer and the tumour cell content. GJB, MB, PS, HS and AJW reported the germline and tumour BRCA1/2 variants tested in the North West Genomic Laboratory Hub. All authors interpreted the data and reviewed the final version of the manuscript.

    • Funding ERW, EJC and DGRE are supported by the Manchester National Institute for Health Research Manchester Biomedical Research Centre (IS-BRC-1215–20007). EJC is supported by a National Institute for Health Research Advanced Fellowship (NIHR300650).

    • 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.