Abstract 571P
Background
Epithelial ovarian cancer (EOC) is one of the most heritable cancers. It is associated with pathogenic variants (PVs) in mismatch repair (MMR) and homologous recombination (HR) genes, including moderate susceptibility gene BRIP1.Background: Epithelial ovarian cancer (EOC) is one of the most heritable cancers. It is associated with pathogenic variants (PVs) in mismatch repair (MMR) and homologous recombination (HR) genes, including moderate susceptibility gene BRIP1.
Methods
We reviewed genetic and clinical data of women with familial EOC referred to our centre between 1993-2021. All underwent BRCA/Lynch screening, then BRCA-negative women underwent exome/EOC panel sequencing or clinical trial genome sequencing. Following detection of BRIP1 c.1045G>C in three unrelated women a case-control study was undertaken, sequencing this and nonsense breast cancer (BC) risk PV BRIP1 c.2392C>T using Sanger sequencing in 3,767 cases and 2,043 controls. Cases were grouped by personal and family history (BC and/or EOC).
Results
From our review of 277 women with familial EOC, 112 different PVs from 12 HR/MMR genes were detected in 150 (54.2%) women. 128 (46.2%) women carried BRCA1/2 PVs. The detection rate in BRCA-negative women was 21.8%, BRIP1 most commonly affected (5.9%) and BRIP1 c.1045G>C detected in three unrelated women. The detection rate of non-BRCA genes decreased as number of affected relatives with BC/EOC increased (OR 8.1, 95% CI=1.5-85.2, P=0.014). Our case-control study found BRIP1 c.1045G>C to be significantly associated with risk of EOC (OR=140.8; 95% CI=23.5-1723.0; P<0.0001) but also BC/EOC (OR=37.7; 95% CI=5.3-444.2; P=0.0001).
Conclusions
This is the largest report of genetic testing in BRCA-negative women with familial EOC undergoing wider testing to date, and first in the UK. A fifth of BRCA-negative women carried a PV in a potentially actionable gene. BRIP1 c.1045G>C, previously described in only one EOC case worldwide, merits further investigation. Its dominant-negative effect may confer a higher risk of EOC than its loss-of-function counterparts. Wider genetic testing of women (including BRIP1) with familial EOC is essential to optimise treatment and EOC prevention. This work highlights the importance of BRIP1, especially in familial EOC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
CRUK Manchester Centre, Prevent breast cancer, NIHR Manchester Biomedical Resource Centre.
Disclosure
All authors have declared no conflicts of interest.