Article

Association of BRCA1 and BRCA2 Mutations With Survival, Chemotherapy Sensitivity, and Gene Mutator Phenotype in Patients With Ovarian Cancer

Department of Obstetrics and Gynaecology, University of Helsinki, Helsinki, Uusimaa, Finland
JAMA The Journal of the American Medical Association (Impact Factor: 30.39). 10/2011; 306(14):1557-65. DOI: 10.1001/jama.2011.1456
Source: PubMed

ABSTRACT Attempts to determine the clinical significance of BRCA1/2 mutations in ovarian cancer have produced conflicting results.
To determine the relationships between BRCA1/2 deficiency (ie, mutation and promoter hypermethylation) and overall survival (OS), progression-free survival (PFS), chemotherapy response, and whole-exome mutation rate in ovarian cancer.
Observational study of multidimensional genomics and clinical data on 316 high-grade serous ovarian cancer cases that were made public between 2009 and 2010 via The Cancer Genome Atlas project.
OS and PFS rates (primary outcomes) and chemotherapy response (secondary outcome).
BRCA2 mutations (29 cases) were associated with significantly better OS (adjusted hazard ratio [HR], 0.33; 95% CI, 0.16-0.69; P = .003 and 5-year OS, 61% for BRCA2-mutated vs 25% for BRCA wild-type cases) and PFS (adjusted HR, 0.40; 95% CI, 0.22-0.74; P = .004 and 3-year PFS, 44% for BRCA2-mutated vs 16% for BRCA wild-type cases), whereas neither BRCA1 mutations (37 cases) nor BRCA1 methylation (33 cases) was associated with prognosis. Moreover, BRCA2 mutations were associated with a significantly higher primary chemotherapy sensitivity rate (100% for BRCA2-mutated vs 82% [P = .02] and 80% [P = .05] for BRCA wild-type and BRCA1-mutated cases, respectively) and longer platinum-free duration (median platinum-free duration, 18.0 months for BRCA2-mutated vs 11.7 [P = .02] and 12.5 [P = .04] months for BRCA wild-type and BRCA1-mutated cases, respectively). BRCA2-mutated, but not BRCA1-mutated cases, exhibited a "mutator phenotype" by containing significantly more mutations than BRCA wild-type cases across the whole exome (median mutation number per sample, 84 for BRCA2-mutated vs 52 for BRCA wild-type cases, false discovery rate <0.1).
Among women with high-grade serous ovarian cancer, BRCA2 mutation, but not BRCA1 deficiency, was associated with improved survival, improved chemotherapy response, and genome instability compared with BRCA wild-type.

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Available from: Ken Hess, Jul 22, 2014
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    • "Individuals with inactivating mutations in BRCA2 exhibit a strong predisposition to cancers of the breast, ovary, and other tissues. However, patients with tumors harboring BRCA2 mutations have an improved prognosis following treatment with platinum-containing and other drugs, compared to patients with tumors with intact BRCA2 genes (Maxwell and Domchek, 2012; Yang et al., 2011). In addition, BRCA2 mutation status leads to differences in metastatic frequency in patients (Bayraktar et al., 2013; James et al., 2009). "
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    ABSTRACT: Tumor cells have unstable genomes relative to non-tumor cells. Decreased DNA integrity resulting from tumor cell instability is important in generating favorable therapeutic indices, and intact DNA repair mediates resistance to therapy. Targeting DNA repair to promote the action of anti-cancer agents is therefore an attractive therapeutic strategy. BRCA2 is involved in homologous recombination repair. BRCA2 defects increase cancer risk but, paradoxically, cancer patients with BRCA2 mutations have better survival rates. We queried TCGA data and found that BRCA2 alterations led to increased survival in patients with ovarian and endometrial cancer. We developed a BRCA2-targeting second-generation antisense oligonucleotide (ASO), which sensitized human lung, ovarian, and breast cancer cells to cisplatin by as much as 60%. BRCA2 ASO treatment overcame acquired cisplatin resistance in head and neck cancer cells, but induced minimal cisplatin sensitivity in non-tumor cells. BRCA2 ASO plus cisplatin reduced respiration as an early event preceding cell death, concurrent with increased glucose uptake without a difference in glycolysis. BRCA2 ASO and cisplatin decreased metastatic frequency in vivo by 77%. These results implicate BRCA2 as a regulator of metastatic frequency and cellular metabolic response following cisplatin treatment. BRCA2 ASO, in combination with cisplatin, is a potential therapeutic anti-cancer agent.
    Molecular Oncology 06/2014; 8(8). DOI:10.1016/j.molonc.2014.05.017 · 5.94 Impact Factor
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    • "Previous analysis by Chiang et al. [26] showed a significant decrease in both PFS and OS among BRCA1 promoter hypermethylated patients. However, these data were not confirmed in the study carried out by Yang et al. [27], in which a positive prognostic effect was observed in patients with BRCA2 mutated tumours but not with BRCA1-mutated or hypermethylated tumours. In particular, among patients with high-grade serous ovarian cancer, BRCA2 mutations but not BRCA1 deficiency (including both BRCA1 mutations and BRCA1 methylation cases) were associated with improved survival, improved chemotherapy response and genome instability compared with BRCA wild-type tumours. "
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    ABSTRACT: Background: Mutations in BRCA1/2 genes are involved in the pathogenesis of breast and ovarian cancer. Inactivation of these genes can also be mediated by hypermethylation of CpGs in the promoter regions. Aim of this study was to analyse the clinical impact of BRCA1 promoter gene methylation status in a homogenous cohort of high-grade serous ovarian cancer (HGSOC) patients. Methods: The cohort included 257 primary HGSOC patients treated by cytoreduction and platinum-based chemotherapy. DNA was extracted from fresh frozen tissue samples. BRCA1 gene promoter methylation rate was assessed using polymerase chain reaction (PCR). Results: 14.8% of patients presented hypermethylation within a selected region of the BRCA1 promoter. The rate of hypermethylation was significantly higher in younger patients (20.8% hypermethylation in the age group <= 58 years versus 8.7% hypermethylation in the age group >58 years; p = 0.008). Optimal tumour debulking could be reached in 63% of patients, without significant differences in the extent of residual disease with respect to the methylation status. No impact of BRCA1 gene promoter methylation status on progression free- and overall-survival rates was found. No significant differences within BRCA1 promoter methylation status between primary and metastatic tissue could be observed. These results on BRCA1 promoter methylation status were also confirmed in a subgroup of 107 patients found negative for BRCA1 exon 11 mutations. Conclusions: Our data suggest that BRCA1 methylation determines the earlier onset of HGSOC. Furthermore our study supports the idea that BRCAness is not only due to mutations but also to epigenetic changes in BRCA1 promoter gene.
    European journal of cancer (Oxford, England: 1990) 05/2014; 50(12). DOI:10.1016/j.ejca.2014.05.001 · 4.82 Impact Factor
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    • "Previous analysis by Chiang et al. [26] showed a significant decrease in both PFS and OS among BRCA1 promoter hypermethylated patients. However, these data were not confirmed in the study carried out by Yang et al. [27], in which a positive prognostic effect was observed in patients with BRCA2 mutated tumours but not with BRCA1-mutated or hypermethylated tumours. In particular, among patients with high-grade serous ovarian cancer, BRCA2 mutations but not BRCA1 deficiency (including both BRCA1 mutations and BRCA1 methylation cases) were associated with improved survival, improved chemotherapy response and genome instability compared with BRCA wild-type tumours. "
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    ABSTRACT: Background Mutations in BRCA1/2 genes are involved in the pathogenesis of breast and ovarian cancer. Inactivation of these genes can also be mediated by hypermethylation of CpGs in the promoter regions. Aim of this study was to analyse the clinical impact of BRCA1 promoter gene methylation status in a homogenous cohort of high-grade serous ovarian cancer (HGSOC) patients. Methods The cohort included 257 primary HGSOC patients treated by cytoreduction and platinum-based chemotherapy. DNA was extracted from fresh frozen tissue samples. BRCA1 gene promoter methylation rate was assessed using polymerase chain reaction (PCR). Results 14.8% of patients presented hypermethylation within a selected region of the BRCA1 promoter. The rate of hypermethylation was significantly higher in younger patients (20.8% hypermethylation in the age group ⩽58 years versus 8.7% hypermethylation in the age group >58 years; p = 0.008). Optimal tumour debulking could be reached in 63% of patients, without significant differences in the extent of residual disease with respect to the methylation status. No impact of BRCA1 gene promoter methylation status on progression free- and overall-survival rates was found. No significant differences within BRCA1 promoter methylation status between primary and metastatic tissue could be observed. These results on BRCA1 promoter methylation status were also confirmed in a subgroup of 107 patients found negative for BRCA1 exon 11 mutations. Conclusions Our data suggest that BRCA1 methylation determines the earlier onset of HGSOC. Furthermore our study supports the idea that BRCAness is not only due to mutations but also to epigenetic changes in BRCA1 promoter gene.
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