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. 2020 Sep;63(5):643-654.
doi: 10.5468/ogs.20033. Epub 2020 Sep 2.

Prevalence of tumor BRCA1 and BRCA2 dysfunction in unselected patients with ovarian cancer

Roshni D Kalachand  1 , Ciaran O'Riain  2 , Sinead Toomey  1 , Aoife Carr  1 , Kirsten M Timms  3 , Sharon O'Toole  4 , Stephen Madden  5 , Mark Bates  4 , John J O'Leary  2 , Noreen Gleeson  4 , Dearbhaile O'Donnell  6 , Liam Grogan  7 , Oscar Breathnach  7 , Angela Farrelly  1 , Britta Stordal  8 , Bryan T Hennessy  1   7   9
Affiliations

Prevalence of tumor BRCA1 and BRCA2 dysfunction in unselected patients with ovarian cancer

Roshni D Kalachand et al. Obstet Gynecol Sci. 2020 Sep.

Abstract

Objective: The therapeutic benefits of poly(ADP-ribose) polymerase inhibitors highlight the need to evaluate BRCA1/2 defects in tubal/ovarian cancer (OC). We sought to determine the pattern and disease characteristics associated with tumor BRCA1/2 mutations and BRCA1 methylation in women with OC.

Methods: We obtained 111 OC specimens from 2 university hospitals and assessed BRCA1/2 mutations and BRCA1 methylation in tumor DNA. The frequency and pattern of BRCA1/2 defects were examined. Associations between patient/disease characteristics and BRCA1/2 defects were ascertained (Fisher's exact test). Platinum-free interval (PFI), progression-free survival (PFS), and overall survival (OS) based on the underlying BRCA1/2 defect were determined (Kaplan-Meier analysis [log-rank test]).

Results: We observed a BRCA1/2 dysfunction rate of 40% (28/70) in high-grade serous tubal/ovarian cancer (HGSC), including 14.3% BRCA1 methylation (n=10), 7.1% BRCA1 mutation (n=5), and 18.6% BRCA2 mutation (n=13). Defects in BRCA1/2 genes were associated with stage III/IV HGSC (BRCA1 methylation: P=0.005 [stage III/IV] and P=0.004 [HGSC]; BRCA1/2 mutation: P=0.03 [stage III/IV] and P<0.001 [HGSC]). Patients with BRCA1/2-mutated cancers showed improved OS (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.43-0.99; P=0.045) and a trend toward improved PFI (HR, 0.48; 95% CI, 0.22-1.06; P=0.07) and PFS (HR, 0.72; 95% CI, 0.51-1.03; P=0.07). No survival differences were observed between BRCA1-methylated and BRCA1/2 wild-type non-BRCA1-methylated cancers.

Conclusion: We observed a high tumor BRCA1/2 dysfunction rate in HGSC with a unique predominance of BRCA2 over BRCA1 mutations. While BRCA1/2 mutations conferred survival benefits in OC, no such association was observed with BRCA1 methylation.

Keywords: BRCA1 methylation; BRCA1 mutation; BRCA2 mutation; Ovarian cancer.

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Conflict of interest statement

Conflict of interest

Roshni D. Kalachand has received conference travel fees from Astra Zeneca. Kirsten M. Timms is an employee of and may hold shares in Myriad Genetics Inc. The other authors have no conflicts of interest to declare.

Figures

Fig. 1.
Fig. 1.
Localization of the identified BRCA1/2 mutations in BRCA1/2 proteins. Numbers on the protein graph correspond to amino acid locations; dashed lines delineate exons. Figure created using ProteinPaint software [16]. OCCR, ovarian cancer cluster region.
Fig. 2.
Fig. 2.
Survival analyses according to tumor-specific BRCA1/2 defect. Platinum-free interval (PFI), progression-free survival (PFS), and overall survival (OS) of patients with International Federation of Gynecology and Obstetrics (FIGO) stage III and IV high-grade serous tubal/ovarian cancer (HGSC). Comparison of patients with BRCA1-methylated HGSC and those with BRCA1/2-mutated HGSC to patients with BRCA1/2 wild-type non-BRCA1-methylated HGSC. In all graphs, blue curves indicate non-BRCA1-methylated; red curves indicate BRCA1-methylated; and green curves indicate BRCA1/2-mutated. HR, hazard ratio; CI, confidence interval.
See this image and copyright information in PMC

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