Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities (original) (raw)
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The Journal of Pathology, 2004
BRCA1 is a putative tumour suppressor gene responsible for a hereditary ovarian cancer syndrome. To clarify the possible involvement of BRCA1 in the development of sporadic ovarian neoplasms, this study analysed the immunohistochemical expression of BRCA1 protein in normal ovarian surface epithelium and 119 epithelial ovarian tumours (19 benign, 24 borderline, and 76 malignant tumours). Loss of heterozygosity (LOH) of BRCA1 was examined using three microsatellite markers to analyse the relationship between BRCA1 expression and alterations of the BRCA1 gene. Methylation of the BRCA1 promoter was also analysed by methylation-specific PCR. In ovarian carcinomas showing heterogeneous expression of BRCA1 protein in the same tumour, LOH and methylation status were analysed using microdissection techniques. Finally, the relationship of BRCA1 expression or its genetic alteration to clinicopathological parameters and patient survival was analysed. Ovarian surface epithelial cells expressed BRCA1 protein. Decreased expression of BRCA1 was found in 16% of benign tumours, 38% of borderline tumours, and 72% of carcinomas. LOH of BRCA1 was demonstrated in no benign tumours, 15% of borderline tumours, and 66% of carcinomas. Methylation of BRCA1 was not detected in benign or borderline tumours, but was present in 31% of carcinomas. Reduced expression of BRCA1 correlated with the presence of gene methylation. The frequency of BRCA1 methylation and LOH was higher in serous carcinomas than in other types. In one of the three serous carcinomas that showed heterogeneous expression of BRCA1, BRCA1-positive borderline-like tumour cells were LOH-positive and methylation-negative, whereas adjacent BRCA1-negative carcinoma cells were LOH-positive and methylation-positive. The prognosis of carcinoma patients did not correlate with BRCA1 expression or genetic status. These findings suggest that reduced expression of BRCA1 protein along with genetic and epigenetic changes of the BRCA1 gene play an important role in the development of sporadic ovarian carcinomas, particularly those of serous histology.
Epigenetic Factors Controlling the BRCA1 and BRCA2 Genes in Sporadic Ovarian Cancer1
2002
Hypermethylation of the BRCA1 promoter has previously been shown to cause reduced mRNA expression in both breast and ovarian cancers. Nothing is yet known of the expression pattern or methylation status of the promoter region of BRCA2 in sporadic ovarian cancer. Whereas our analysis of 30 sporadic ovarian carcinomas showed a statistically signifi- cant reduction of BRCA1 mRNA expression (P
Prevalence of tumor BRCA1 and BRCA2 dysfunction in unselected patients with ovarian cancer
Obstetrics & Gynecology Science, 2020
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), progressionfree 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.
Prevalence of tumor BRCA1 and BRCA2 dysfunction in unselected patients with ovarian cancer
Obstetrics & gynecology science, 2020
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), progressionfree 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.
BRCA1 promoter hypermethylation and protein expression in ovarian carcinoma—an Indian study
Tumor Biology, 2014
Mounting evidences suggest that aberrant methylation of CpG islands is a major pathway leading to the inactivation of tumour suppressor genes and the development of cancer. The aim of the current study was to examine the prevalence of the promoter hypermethylation and protein expression of the BRCA1 gene in epithelial ovarian carcinoma (EOC) to understand the role of epigenetic silencing in ovarian carcinogenesis. We studied the promoter methylation of the BRCA1 gene by methylationspecific PCR in a cohort of 88 patients with EOC, 14 low malignant potential (LMP) tumours and 20 patients with benign tumours of the ovary. The expression of the BRCA1 protein by immunohistochemical analysis was carried out in a subset of 64 EOCs, 10 LMP tumours, 10 benign tumours and 5 normal ovarian tissues. The frequencies of methylation in EOCs and LMP tumours were 51.2 and 57 %, respectively, significantly higher (p=0.000 and p=0.001) in comparison to benign tumours and normal ovarian tissue where no methylation was seen. Expression of BRCA1 was significantly lower in EOCs (p= 0.003). Lack of protein expression correlated with tumour grade and type. The methylation status correlated well with downregulation of BRCA1 expression. Our results clearly demonstrate that hypermethylation of BRCA1 promoter is a frequent event in ovarian cancer. These data support the hypothesis that BRCA1 promoter methylation plays an important role in the functional inactivation of BRCA1. Follow-up clinical data will reveal the impact of BRCA1 methylation on survival.
BRCA1 Promoter Region Hypermethylation in Ovarian Carcinoma: A Population-based Study1
2000
There is a clear association between germ-line BRCA1 mutations and inherited ovarian cancer; however, the association between BRCA1 mutations and sporadic ovarian cancer remains ambiguous. The frequency of BRCA1 promoter hypermethylation as an epigenetic means of BRCA1 inactivation was determined for a large, population-based cohort of ovarian cancer patients. BRCA1 promoter hypermethylation was determined by methylation-specific restriction digestion of tumor DNA, followed by Southern blot analysis and confirmed by methylation-specific PCR. BRCA1 promoter hypermethylation was observed in 12 of 98 ovarian tumors. BRCA1 methylation status of the primary tumor was conserved in six recurrent tumors after interim chemotherapy. None of the 12 tumors with BRCA1 promoter hypermethylation demonstrated BRCA1 protein expression by immunohistochemistry. BRCA1 methylation was only seen in ovarian cancer patients without a family history suggestive of a breast/ ovarian cancer syndrome. Therefore, the 12 BRCA1 methylated tumors represented 15% (12 of 81) of the sporadic cancers analyzed in this study. Although the clinical significance of BRCA1 promoter hypermethylation is yet to be determined, promoter hypermethylation may be an alternative to mutation in causing the inactivation of the BRCA1 tumor suppressor gene in sporadic ovarian cancer.
Journal of Human Genetics
Poly-ADP-ribose-polymerase inhibitor (PARPi) treatment is indicated for advanced-stage ovarian tumors with BRCA1/2 deficiency. The “BRCAness” status is thought to be attributed to a tumor phenotype associated with a specific epigenomic DNA methylation profile. Here, we examined the diagnostic impact of combined BRCA1/2 sequence, copy number, and promoter DNA methylation analysis, and evaluated whether genomic DNA methylation patterns can predict the BRCAness in ovarian tumors. DNA sequencing of 172 human tissue samples of advanced-stage ovarian adenocarcinoma identified 36 samples with a clinically significant tier 1/2 sequence variants (point mutations and in/dels) and 9 samples with a CNV causing a loss of function in BRCA1/2. DNA methylation analysis of the promoter of BRCA1/2 identified promoter hypermethylation of BRCA1 in two mutation-negative samples. Computational modeling of genome-wide methylation markers, measured using Infinium EPIC arrays, resulted in a total accuracy o...
The BRCA Gene in Epithelial Ovarian Cancer
Cancers, 2022
Epithelial ovarian cancer (EOC) is still the most lethal gynecological cancer. Germline alterations in breast cancer 1 (gBRCA1) and breast cancer 2 (gBRCA2) genes have been identified in up to 18% of women diagnosed with EOC, and somatic mutations are found in an additional 7%. Testing of BRCA at the primary diagnosis of patients with EOC is recommended due to the implications in the genomic counseling of the patients and their families, as well as for the therapeutic implications. Indeed, the introduction of poly-(ADP ribose) polymerase inhibitors (PARPis) has changed the natural history of patients harboring a mutation in BRCA, and has resulted in a new era in the treatment of patients with ovarian cancer harboring a BRCA mutation.