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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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    _Manuscript_tBRCA_LR_v5.docx
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    Authors
    Morgan, Robert David
    Burghel, G. J.
    Flaum, Nicola
    Bulman, M.
    Smith, P.
    Clamp, Andrew R
    Hasan, Jurjees
    Mitchell, Claire L
    Salih, Zena|Woodward, E. R.
    Lalloo, F.
    Shaw, J.
    Desai, Sudha
    Crosbie, E. J.
    Edmondson, R. J.
    Schlecht, H.
    Wallace, A. J.
    Jayson, Gordon C
    Evans, D. G. R.
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    Affiliation
    Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
    Issue Date
    2022
    
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    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.
    Citation
    Morgan RD, Burghel GJ, Flaum N, Bulman M, Smith P, Clamp AR, et al. Predicting the likelihood of a BRCA1/2 pathogenic variant being somatic by testing only tumour DNA in non-mucinous high-grade epithelial ovarian cancer. Journal of Clinical Pathology. BMJ; 2022.
    Journal
    Journal of Clinical Pathology
    URI
    http://hdl.handle.net/10541/625390
    DOI
    10.1136/jcp-2022-208369
    PubMed ID
    35738887
    Additional Links
    https://dx.doi.org/10.1136/jcp-2022-208369
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1136/jcp-2022-208369
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    All Christie Publications

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