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
- Biomarkers, Tumor
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
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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.
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