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

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.

• Authors: Robert D Morgan, George J Burghel, Nicola Flaum, Michael Bulman, Philip Smith, Andrew R Clamp, Jurjees Hasan, Claire Mitchell, Zena Salih, Emma R Woodward, Fiona Lalloo, Joseph Shaw, Sudha Desai, Emma J Crosbie, Richard J Edmondson, Helene Schlecht, Andrew J Wallace, Gordon C Jayson, D Gareth R Evans
• Journal: Journal of clinical pathology (J Clin Pathol) Vol. 76 Issue 10 Pg. 684-689 (Oct 2023) ISSN: 1472-4146 [Electronic] England
• PMID: 35738887 (Publication Type: Observational Study, Journal Article)
• Copyright: © Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• BRCA1 protein, human
• BRCA1 Protein
• BRCA2 protein, human
• BRCA2 Protein
• DNA, Neoplasm

Topics

• Humans
• Female
• Carcinoma, Ovarian Epithelial (genetics)
• BRCA1 Protein (genetics)
• Genetic Testing
• BRCA2 Protein (genetics)
• Germ-Line Mutation
• DNA, Neoplasm
• Ovarian Neoplasms (diagnosis, genetics)