Abstract
National guidelines recommend testing all cases of non-mucinous epithelial ovarian cancer (NMEOC) for germline (blood) and somatic (tumour) BRCA1/2 pathogenic variants (PVs). We performed paired germline and somatic BRCA1/2 testing in consecutive cases of NMEOC (n = 388) to validate guidelines. Thirty-four somatic BRCA1/2 (sBRCA) PVs (9.7%) were detected in 350 cases with germline BRCA1/2 (gBRCA) wild-type. All sBRCA PVs were detected in non-familial cases. By analysing our regional germline BRCA1/2 database there were 92/1114 (8.3%) gBRCA PVs detected in non-familial cases (only 3% ≥70 years old) and 245/641 (38.2%) in familial cases. Germline non-familial cases were dominated by BRCA2 in older women (8/271 ≥ 70 years old, all BRCA2). The ratio of sBRCA-to-gBRCA was ≤1.0 in women aged <70 years old, compared to 5.2 in women aged ≥70 years old (P = 0.005). The likelihood of missed germline BRCA1/2 PVs (copy-number variants missed on most somatic assays) by testing only tumour DNA was 0.4% in women aged ≥70 years old. We recommend reflex tumour BRCA1/2 testing in all NMEOC cases, and that gBRCA testing is not required for women aged ≥70 years old with no identifiable tumour BRCA1/2 PV and/or family history of breast, ovarian, prostate and/or pancreatic cancer.
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Acknowledgements
ERW and DGRE are supported by the Manchester National Institute for Health Research (NIHR) Manchester Biomedical Research Centre (IS-BRC-1215-20007). EJC is supported by a NIHR Advanced Fellowship (NIHR300650). NF is supported by CRUK via the funding to Cancer Research UK Manchester Centre: [C147/A18083] and [C147/A25254].
Funding
The tumour BRCA1/2 testing service was funded by AstraZeneca and Merck Sharp & Dohme, who gave permission to publish the data. Neither company had any influence in the writing of the manuscript or the views expressed by the authors.
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RDM and DGRE designed and initiated the study. RDM, NF, ARC, JH, CLM, ZS, ERW, FL, EJC, RJE, GCJ and DGRE gained consent for germline and tumour BRCA1/2 testing. GJB, MB, PS and AJW reported all germline and tumour BRCA1/2 results. All authors interpreted the data and reviewed the final version of the manuscript.
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RDM, GJB, NF, MB, PS, JH, CLM, ZS, ERW, FL, EJC, RJE, AJW and DGRE declare no competing interests. GCJ declares research funding from AstraZeneca for investigator-led clinical trials. ARC declares research funding and advisory boards fees from AstraZeneca, and speaker and advisory board fees from Clovis Oncology.
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All women included in this study provided informed consent to undergo germline and tumour BRCA1/2 testing. The germline BRCA1/2 database is approved by North Manchester Research Ethics Committee (08/H1006/77). The Genetic Variants in Gynaecological Cancer database is approved by the Christie NHS Foundation Trust (59).
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Morgan, R.D., Burghel, G.J., Flaum, N. et al. BRCA1/2 in non-mucinous epithelial ovarian cancer: tumour with or without germline testing?. Br J Cancer 127, 163–167 (2022). https://doi.org/10.1038/s41416-022-01773-y
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DOI: https://doi.org/10.1038/s41416-022-01773-y