Press, J. Z. et al. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer 8, 17

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
BMC Cancer (Impact Factor: 3.36). 02/2008; 8(1):17. DOI: 10.1186/1471-2407-8-17
Source: PubMed


Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas.
A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry.
Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumours were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumours with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1.
High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

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    • "lanes 1 and 3). This suggests that promoter methylation-associated BRCA1 depletion, a relatively common event in sporadic BRCA1 +/+ breast and ovarian cancers (Press et al. 2008; Dworkin et al. 2009), can give rise to chronically enhanced sensitivity to a-amanitin or other transcription inhibitors. If so, deficient BRCA1-driven, transcriptionassociated DNA damage control might prove to be a specific molecular vulnerability or even a therapeutic target in this setting. "
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    ABSTRACT: BRCA1 is a breast and ovarian tumor suppressor. Given its numerous incompletely understood functions and the possibility that more exist, we performed complementary systematic screens in search of new BRCA1 protein-interacting partners. New BRCA1 functions and/or a better understanding of existing ones were sought. Among the new interacting proteins identified, genetic interactions were detected between BRCA1 and four of the interactors: TONSL, SETX, TCEANC, and TCEA2. Genetic interactions were also detected between BRCA1 and certain interactors of TONSL, including both members of the FACT complex. From these results, a new BRCA1 function in the response to transcription-associated DNA damage was detected. Specifically, new roles for BRCA1 in the restart of transcription after UV damage and in preventing or repairing damage caused by stabilized R loops were identified. These roles are likely carried out together with some of the newly identified interactors. This new function may be important in BRCA1 tumor suppression, since the expression of several interactors, including some of the above-noted transcription proteins, is repeatedly aberrant in both breast and ovarian cancers.
    Full-text · Article · Sep 2014 · Genes & Development
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    • "In healthy individuals, the regulatory region of the full active BRCA gene is demethylated. Methylation process may cause a downregulation of the protein leading to gene dysfunction [5] [6] [7] [8] [9] [10] [11] [12]. "
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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.
    Full-text · Article · May 2014 · European journal of cancer (Oxford, England: 1990)
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    • "Altered BRCA function in HGSC does not only occur in the setting of hereditary disease. Dysfunction of BRCA1 or BRCA2 is prevalent in patients with HGSC via 6% somatic mutations (5, 33–35); 13–31% promoter hypermethylation (5, 36–38); 7.9–17% amplification of EMSY (5, 39, 40); or 13.2% promoter hypermethylation of FANCF (41). The sum of these genomic alterations predominantly in the HR pathway of HGSC has led to determining the “BRCAness” profile in patients (42, 43). "
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    ABSTRACT: Women who have an inherited mutation in the BRCA1 or BRCA2 genes have a substantial increased lifetime risk of developing epithelial ovarian cancer (EOC), and epidemiological factors related to parity, ovulation, and hormone regulation have a dramatic effect on the risk in both BRCA mutation carriers and non-carriers. The most common and most aggressive histotype of EOC, high-grade serous carcinoma (HGSC), is also the histotype associated with germline BRCA mutations. In recent years, evidence has emerged indicating that the likely tissue of origin of HGSC is the fallopian tube. We have reviewed, what is known about the fallopian tube in BRCA mutation carriers at both the transcriptional and translational aspect of their biology. We propose that changes of the transcriptome in BRCA heterozygotes reflect an altered response to the ovulatory stresses from the microenvironment, which may include the post-ovulation inflammatory response and altered reproductive hormone physiology.
    Full-text · Article · Jan 2014 · Frontiers in Oncology
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