Assessment of predisposition to familial non-mucinous epithelial ovarian cancer

Student thesis: Phd


Background: Epithelial ovarian cancer (EOC) is associated with pathogenic variants (PVs) in homologous recombination and mismatch repair genes, but much familial risk is still unexplained. Polygenic risk scores (PRSs) for EOC have been created but not validated or integrated. BRCA1/2 testing has become mainstreamed since development of PARP inhibitors, which improve survival in BRCA1/2-heterozygote women with EOC. Risk-reducing salpingo-oophorectomy (RRSO) is used to reduce EOC/primary peritoneal cancer (PPC) risk in BRCA1/2-heterozygotes. Understanding of familial ovarian cancer and risk prediction can be improved. Methods: 1) Clinical/genetic data from familial EOC patients (proband plus ≥1 affected relative) were analysed. 2) Variant BRIP1 c.1045G>C was sequenced in 3,767 cases and 2,043 controls, grouped by breast/ovarian cancer history. 3) SNPs were genotyped and PRSs constructed for 986 EOC cases and 1,452 controls (OC study) and 300 BRCA1/2-heterozygous cases and 355 controls (BRCA study). PRSs were assessed using logistic regression and combined with clinical data. 4) BRCA1/2 testing and detection rates since mainstreaming were assessed/ and EOC/PPC rates in BRCA1/2-heterozygotes undergoing RRSO (891 cases) and 1,302 controls. Results: Of 277 women with familial EOC, 46.2% were BRCA1/2-heterozygotes, PVs were found in 21.8% BRCA1/2-wild type women, with BRIP1 most affected (5.9%). BRIP1 c.1045G>C was associated with familial EOC (OR=140.8; 95% CI 23.5-1723.0, p C with a dominant-negative effect may confer a higher EOC risk than loss of function variants. EOC PRS models were successfully validated and optimised combining with risk factor data, however the contribution of PRS to risk models is small. Larger prospective studies could assess if combined-PRS models inform risk-reducing decisions. Mainstream BRCA1/2 testing enables detection to select EOC patients for PARP inhibitors, but poor uptake of cascade testing needs further examination and improvement. RRSO reduces the overall risk of PPC by a far greater reduction than previously described.
Date of Award1 Aug 2023
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorDafydd Evans (Supervisor), Emma Crosbie (Supervisor), Miriam Smith (Supervisor) & Richard Edmondson (Supervisor)


  • ovarian cancer, familial cancer, BRCA, homologous recombination, mismatch repair, cancer predisposition, risk-reduction

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