Obstet Gynecol Sci.  2020 Sep;63(5):643-654. 10.5468/ogs.20033.

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

• Kalachand RD
• O’Riain C
• Toomey S
• Carr A
• Timms KM
• O’Toole S
• Madden S
• Bates M
• O’Leary JJ
• Gleeson N
• O’Donnell D
• Grogan L
• Breathnach O
• Farrelly A
• Stordal B
• Hennessy BT

• KMID: 2506507
• DOI: http://doi.org/10.5468/ogs.20033

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.

Keyword

Ovarian cancer; methylation; mutation; mutation

Figure

• 

  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.

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  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.

Reference

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