BRCA1; breast cancer 1, early onset (17q21)

Gene Summary

Gene:BRCA1; breast cancer 1, early onset
Summary:This gene encodes a nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:breast cancer type 1 susceptibility protein
Updated:12 July, 2014


What does this gene/protein do?
BRCA1 is implicated in:
- androgen receptor binding
- androgen receptor signaling pathway
- apoptotic process
- brain development
- BRCA1-A complex
- BRCA1-BARD1 complex
- cell cycle
- cellular response to indole-3-methanol
- centrosome cycle
- chordate embryonic development
- chromosome
- chromosome segregation
- condensed nuclear chromosome
- damaged DNA binding
- DNA binding
- DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator
- DNA repair
- DNA replication
- dosage compensation by inactivation of X chromosome
- double-strand break repair
- double-strand break repair via homologous recombination
- enzyme binding
- fatty acid biosynthetic process
- filamentous actin
- focal adhesion
- G2/M transition DNA damage checkpoint
- gamma-tubulin ring complex
- intrinsic apoptotic signaling pathway in response to DNA damage response
- mitochondrial matrix
- negative regulation of centriole replication
- negative regulation of fatty acid biosynthetic process
- negative regulation of histone H3-K9 methylation
- negative regulation of transcription, DNA-dependent
- nucleoplasm
- nucleus
- plasma membrane
- positive regulation of cell cycle arrest
- positive regulation of DNA repair
- positive regulation of histone acetylation
- positive regulation of histone H3-K4 methylation
- positive regulation of histone H3-K9 acetylation
- positive regulation of histone H4-K16 acetylation
- positive regulation of histone H4-K20 methylation
- positive regulation of protein ubiquitination
- positive regulation of transcription from RNA polymerase II promoter
- positive regulation of transcription, DNA-dependent
- postreplication repair
- protein autoubiquitination
- protein binding
- protein complex
- protein K6-linked ubiquitination
- protein ubiquitination
- regulation of apoptotic process
- regulation of cell motility
- regulation of cell proliferation
- regulation of transcription from RNA polymerase II promoter
- regulation of transcription from RNA polymerase III promoter
- response to DNA damage stimulus
- response to estradiol stimulus
- response to estrogen stimulus
- response to ionizing radiation
- response to lipid
- response to nutrient
- ribonucleoprotein complex
- RNA binding
- ruffle
- substrate adhesion-dependent cell spreading
- transcription coactivator activity
- transcription regulatory region DNA binding
- tubulin binding
- ubiquitin ligase complex
- ubiquitin protein ligase binding
- ubiquitin-protein ligase activity
- zinc ion binding
Data from Gene Ontology via CGAP


What pathways are this gene/protein implicaed in?
- ATM Signaling Pathway BIOCARTA
- BRCA1-dependent Ub-ligase activity BIOCARTA
- CARM1 and Regulation of the Estrogen Receptor BIOCARTA
- Cell Cycle BIOCARTA
- Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility BIOCARTA
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

BRCA1 is a breast cancer susceptibility gene that was first identified in 1994. People carrying a mutation (abnormality) in this gene are at an increased risk of breast or ovarian cancer. The normal gene plays a role in repairing breaks in DNA. However, when the gene is mutated it is thought that this repair function may become disabled thus leading to more DNA replication errors and cancerous growth.

Research Indicators

Publications Per Year (1989-2014)
Graph generated 12 July 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 12 July, 2014 using data from PubMed, MeSH and CancerIndex


BRCA1 mutations in Breast Cancer

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185delAG mutation (c.68_69delAG) in BRCA1
The 185delAG mutation (c.68_69delAG; ter39) in the BRCA1 gene is a founder mutation carried by approximately 1% of the Jewish Ashkenazi population.
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BRCA1 germliine mutation and increased risk of Colorectal Cancer?
There have been conflicting results regarding the risk of colorectal cancer confered by germline mutations of BRCA1 & BRCA2. In a follow-up study of 7015 women with a BRCA mutations Phelan et al (2014) found significantly increased risk of colorectal cancer in female carriers of BRCA1 mutations below the age of 50 years but not in women with BRCA2 mutations or in older women.
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Hereditary Breast and Ovarian Cancer Syndrome
An Autosomal dominant hereditary cancer syndrome in which a mutation most often in either BRCA1 or BRCA2 is associated with a significantly increased risk for breast and ovarian cancers. [MeSH]
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Related Links

Latest Publications: BRCA1 (cancer-related)

Enginler SO, Akış I, Toydemir TS, et al.
Genetic variations of BRCA1 and BRCA2 genes in dogs with mammary tumours.
Vet Res Commun. 2014; 38(1):21-7 [PubMed] Related Publications
Mammary tumours are the most common tumour type in female dogs. The formation of the mammary tumours is multifactorial but the high incidence of tumour disease in certain canine breeds suggests a strong genetic component. BRCA1 and BRCA2 are the most important genes significantly associated with mammary tumours. The aim of this study was to determine the association between the variations of these two genes and canine mammary tumours. 5′-untranslated region, intron 8 and exon 9 of BRCA1 and exons 12, 24, 27 of BRCA2 were sequenced in order to detect the genetic variations. In addition to six previously identified polymorphisms, six novel single nucleotide polymorphisms (SNPs) were detected. Five of the coding SNPs were synonymous and three of them were non-synonymous. The comparison of the sequences from 25 mammary tumour bearing and 10 tumour free dogs suggested that the two SNPs in intron 8 and exon 9 of BRCA1 and two SNPs in exon 24 and exon 27 of BRCA2, which are firstly identified in this study, might be associated with mammary tumour development in dogs. Especially one SNP in exon 9 of BRCA1 and one SNP in exon 24 of BRCA2 were found to be significantly associated with canine mammary tumours.

Related: BRCA2 Polymorphisms

Bookman MA
On the road to PARPi-platin.
J Natl Cancer Inst. 2014; 106(6):dju119 [PubMed] Related Publications

Related: Ovarian Cancer

Lee JM, Hays JL, Annunziata CM, et al.
Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses.
J Natl Cancer Inst. 2014; 106(6):dju089 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
BACKGROUND: Olaparib has single-agent activity against breast/ovarian cancer (BrCa/OvCa) in germline BRCA1 or BRCA2 mutation carriers (gBRCAm). We hypothesized addition of olaparib to carboplatin can be administered safely and yield preliminary clinical activity.
METHODS: Eligible patients had measurable or evaluable disease, gBRCAm, and good end-organ function. A 3 + 3 dose escalation tested daily oral capsule olaparib (100 or 200mg every 12 hours; dose level1 or 2) with carboplatin area under the curve (AUC) on day 8 (AUC3 day 8), then every 21 days. For dose levels 3 to 6, patients were given olaparib days 1 to 7 at 200 and 400 mg every 12 hours, with carboplatin AUC3 to 5 on day 1 or 2 every 21 days; a maximum of eight combination cycles were permitted, after which daily maintenance of olaparib 400mg every12 hours continued until progression. Dose-limiting toxicity was defined in the first two cycles. Peripheral blood mononuclear cells were collected for polymorphism analysis and polyADP-ribose incorporation. Paired tumor biopsies (before/after cycle 1) were obtained for biomarker proteomics and apoptosis endpoints.
RESULTS: Forty-five women (37 OvCa/8 BrCa) were treated. Dose-limiting toxicity was not reached on the intermittent schedule. Expansion proceeded with olaparib 400mg every 12 hours on days 1 to 7/carboplatin AUC5. Grade 3/4 adverse events included neutropenia (42.2%), thrombocytopenia (20.0%), and anemia (15.6%). Responses included 1 complete response (1 BrCa; 23 months) and 21 partial responses (50.0%; 15 OvCa; 6 BrCa; median = 16 [4 to >45] in OvCa and 10 [6 to >40] months in BrCa). Proteomic analysis suggests high pretreatment pS209-eIF4E and FOXO3a correlated with duration of response (two-sided P < .001; Pearson's R (2) = 0.94).
CONCLUSIONS: Olaparib capsules 400mg every 12 hours on days 1 to 7/carboplatin AUC5 is safe and has activity in gBRCAm BrCa/OvCa patients. Exploratory translational studies indicate pretreatment tissue FOXO3a expression may be predictive for response to therapy, requiring prospective validation.

Related: Breast Cancer Carboplatin Ovarian Cancer

Friebel TM, Domchek SM, Rebbeck TR
Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis.
J Natl Cancer Inst. 2014; 106(6):dju091 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
BACKGROUND: There is substantial variability in cancer risk in women who have inherited a BRCA1 or BRCA2 (BRCA1/2) mutation. Numerous factors have been hypothesized to modify these risks, but studies are of variable quality, and it remains unclear which of these may be of value in clinical risk assessment.
METHODS: PubMed and Web of Science databases were searched for articles published through September 2013. Fixed effects meta-analysis was done using the hazard ratios and/or odds ratios to estimate the pooled effect estimates (ES) and 95% confidence intervals (CIs) to identify factors that are associated with cancer risk modification in BRCA1/2 mutation carriers.
RESULTS: We identified 44 nonoverlapping studies that met predefined quality criteria. Sufficient evidence is available to make clinically relevant inferences about a number of cancer risk modifiers. The only variable examined that produced a probable association was late age at first live birth, a meta-analysis showed a decrease in the risk of breast cancer in BRCA1 mutation carriers with women aged 30 years or older vs. women younger than 30 years (ES = 0.65; 95% CI =0.42 to 0.99). The same was shown for women aged 25 to 29 years versus those aged less than 25 years (ES = 0.69; 95% CI = 0.48 to 0.99). Breastfeeding and tubal ligation were associated with reduced ovarian cancer risk in BRCA1 mutation carriers; oral contraceptives were associated with reduced risk among BRCA1/2 mutation carriers. Smoking was associated with increased breast cancer risk in BRCA2 mutation carriers only.
CONCLUSIONS: Data assessing many potential risk modifiers are inadequate, and many have not been externally validated. Although additional studies are required to confirm some associations, sufficient information is available for some risk factors to be used in risk counseling or lifestyle modification to minimize cancer risk in BRCA1/2 mutation carriers

Related: Breast Cancer Ovarian Cancer

Rabban JT, Garg K, Crawford B, et al.
Early detection of high-grade tubal serous carcinoma in women at low risk for hereditary breast and ovarian cancer syndrome by systematic examination of fallopian tubes incidentally removed during benign surgery.
Am J Surg Pathol. 2014; 38(6):729-42 [PubMed] Related Publications
Early detection of sporadic pelvic serous carcinoma remains an elusive goal. In women at high risk for hereditary breast and ovarian cancer syndrome who undergo prophylactic salpingectomy, systematic pathologic examination of the fallopian tubes will detect occult tubal cancer, mostly in the fimbriae, of a minority of women. Such tubal cancers are the putative precursor to advanced-stage pelvic cancer. We hypothesized that early tubal cancer detection can also be accomplished in women at low risk using a similar approach. In this study, we performed complete and systematic examination of the fallopian tubes removed during surgery performed for benign indications. Among 522 women, 4 cases of serous tubal intraepithelial carcinoma (STIC) were identified. Three of these cases would have gone undetected using the current standard of care of sampling only a single random section of the tube. The fourth case was accompanied by occult ovarian carcinoma. The fimbriae contained STIC in 3 of the 4 cases and atypical mucosa in 1 case in which the STIC was in the nonfimbriated portion of the tube. The morphologic and immunohistochemical features (aberrant p53 and MIB-1) of these STICs were similar to those expected in high-risk women. All 4 patients with STIC underwent BRCA1 and BRCA2 gene testing; no germline mutations were identified in any patient. An additional 11 specimens contained atypical mucosal proliferations that fell short of morphologic and immunohistochemical criteria for STIC. Two of these 11 fulfilled criteria for a serous tubal intraepithelial lesion, and the remaining atypical proliferations exhibited normal p53 and MIB-1. For most specimens, the fimbriae could be completely submitted in 1 or 2 cassettes per tube. These results demonstrate that systematic examination of the tubal fimbriae can serve as a form of early detection of sporadic tubal cancer without incurring significant labor or cost. We propose that the tubal fimbriae should be completely examined in all patients undergoing benign surgery even if there are no clinical features to suggest risk for hereditary breast and ovarian cancer syndrome.

Related: Cancer Screening and Early Detection Fallopian Tube Cancer MKI67 TP53

Brody JG, Kripke ML, Kavanaugh-Lynch MH, et al.
Breast cancer and environmental research.
Science. 2014; 344(6184):577 [PubMed] Related Publications

Related: Breast Cancer

Cartwright-Smith L
Patenting genes: what does Association for Molecular Pathology v. Myriad Genetics mean for genetic testing and research?
Public Health Rep. 2014; 129(3):289-92 [PubMed] Article available free on PMC after 01/05/2015 Related Publications

Mai PL, Loud JT, Greene MH
A major step forward for BRCA1/2-related cancer risk management.
J Clin Oncol. 2014; 32(15):1531-3 [PubMed] Related Publications

Makowski L, Zhou C, Zhong Y, et al.
Obesity increases tumor aggressiveness in a genetically engineered mouse model of serous ovarian cancer.
Gynecol Oncol. 2014; 133(1):90-7 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
OBJECTIVES: Obesity is associated with increased risk and worse outcomes for ovarian cancer. Thus, we examined the effects of obesity on ovarian cancer progression in a genetically engineered mouse model of serous ovarian cancer.
METHODS: We utilized a unique serous ovarian cancer mouse model that specifically deletes the tumor suppressor genes, Brca1 and p53, and inactivates the retinoblastoma (Rb) proteins in adult ovarian surface epithelial cells, via injection of an adenoviral vector expressing Cre (AdCre) into the ovarian bursa cavity of adult female mice (KpB mouse model). KpB mice were subjected to a 60% calories-derived from fat in a high fat diet (HFD) versus 10% calories from fat in a low fat diet (LFD) to mimic diet-induced obesity. Tumors were isolated at 6 months after AdCre injection and evaluated histologically. Untargeted metabolomic and gene expression profiling was performed to assess differences in the ovarian tumors from obese versus non-obese KpB mice.
RESULTS: At sacrifice, mice on the HFD (obese) were twice the weight of mice on the LFD (non-obese) (51g versus 31g, p=0.0003). Ovarian tumors were significantly larger in the obese versus non-obese mice (3.7cm(2) versus 1.2cm(2), p=0.0065). Gene expression and metabolomic profiling indicated statistically significant differences between the ovarian tumors from the obese versus non-obese mice, including metabolically relevant pathways.

Related: Ovarian Cancer

Venkitaraman AR
Cancer suppression by the chromosome custodians, BRCA1 and BRCA2.
Science. 2014; 343(6178):1470-5 [PubMed] Related Publications
Germline mutations in BRCA1 and BRCA2 predispose to common human malignancies, most notably tumors of the breast and ovaries. The proteins encoded by these genes have been implicated in a plethora of biochemical interactions and biological functions, confounding attempts to coherently explain how their inactivation promotes carcinogenesis. Here, I argue that tumor suppression by BRCA1 and BRCA2 originates from their fundamental role in controlling the assembly and activity of macromolecular complexes that monitor chromosome duplication, maintenance, and segregation across the cell cycle. A tumor-suppressive role for the BRCA proteins as "chromosome custodians" helps to explain the clinical features of cancer susceptibility after their inactivation, provides foundations for the rational therapy of BRCA-deficient cancers, and offers general insights into the mechanisms opposing early steps in human carcinogenesis.

Related: Breast Cancer

Couch FJ, Nathanson KL, Offit K
Two decades after BRCA: setting paradigms in personalized cancer care and prevention.
Science. 2014; 343(6178):1466-70 [PubMed] Article available free on PMC after 28/09/2014 Related Publications
The cloning of the breast cancer susceptibility genes BRCA1 and BRCA2 nearly two decades ago helped set in motion an avalanche of research exploring how genomic information can be optimally applied to identify and clinically care for individuals with a high risk of developing cancer. Genetic testing for mutations in BRCA1, BRCA2, and other breast cancer susceptibility genes has since proved to be a valuable tool for determining eligibility for enhanced screening and prevention strategies, as well as for identifying patients most likely to benefit from a targeted therapy. Here, we discuss the landscape of inherited mutations and sequence variants in BRCA1 and BRCA2, the complexities of determining disease risk when the pathogenicity of sequence variants is uncertain, and current strategies for clinical management of women who carry BRCA1/2 mutations.

Related: Breast Cancer

King MC
"The race" to clone BRCA1.
Science. 2014; 343(6178):1462-5 [PubMed] Related Publications
The existence of BRCA1 was proven in 1990 by mapping predisposition to young-onset breast cancer in families to chromosome 17q21. Knowing that such a gene existed and approximately where it lay triggered efforts by public and private groups to clone and sequence it. The press baptized the competition "the race" and reported on it in detail for the next 4 years. BRCA1 was positionally cloned in September 1994. Twenty years later, I reflect on "the race" and its consequences for breast cancer prevention and treatment.

Related: Breast Cancer Chromosome 17

Kean S
Breast cancer. The 'other' breast cancer genes.
Science. 2014; 343(6178):1457-9 [PubMed] Related Publications

Kiberstis P, Roberts L
Breast cancer. A race still unfinished. Introduction.
Science. 2014; 343(6178):1451 [PubMed] Related Publications

Taylor A, Tischkowitz M
Informed decision-making is the key in women at high risk of breast cancer.
Eur J Surg Oncol. 2014; 40(6):667-9 [PubMed] Related Publications

Related: Breast Cancer

Bookman MA, Gilks CB, Kohn EC, et al.
Better therapeutic trials in ovarian cancer.
J Natl Cancer Inst. 2014; 106(4):dju029 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
The Ovarian Task Force of the Gynecologic Cancer Steering Committee convened a clinical trials planning meeting on October 28-29, 2011, with the goals to identify key tumor types, associated molecular pathways, and biomarkers for targeted drug intervention; review strategies to improve early-phase screening, therapeutic evaluation, and comparison of new agents; and optimize design of randomized trials in response to an evolving landscape of scientific, regulatory, and funding priorities. The meeting was attended by international clinical and translational investigators, pharmaceutical industry representatives, government regulators, and patient advocates. Panel discussions focused on disease types, early-phase trials, and randomized trials. A manuscript team summarized the discussions and assisted with formulating key recommendations. A more integrated and efficient approach for screening new agents using smaller selective randomized trials in specific disease-type settings was endorsed, together with collaborative funding models between industry and the evolving national clinical trials network, as well as efforts to enhance public awareness and study enrollment through advocacy.

Related: Ovarian Cancer USA

Pilgrim S, Pain S
Bilateral risk-reducing mastectomy is the safest strategy in BRCA1 carriers.
Eur J Surg Oncol. 2014; 40(6):670-2 [PubMed] Related Publications

Liu JF, Konstantinopoulos PA, Matulonis UA
PARP inhibitors in ovarian cancer: current status and future promise.
Gynecol Oncol. 2014; 133(2):362-9 [PubMed] Related Publications
Clinical investigation of poly(ADP-ribose) polymerase (PARP) inhibitors for ovarian cancer treatment has rapidly evolved from observations of single-agent in vitro activity of these agents in BRCA-deficient cancer cells in 2005 to the initiation of multiple phase III studies in 2013. With clinical trial design and treatment of ovarian cancer increasingly based on histological and molecular characteristics, PARP inhibitors are on the horizon of becoming the first biologic agents to be used to treat ovarian cancer based upon pre-selection characteristics of the patient's cancer. PARP inhibitors are most active in ovarian cancers that have defects or aberrations in DNA repair; use of these agents has been of particular interest in high grade serous cancers (HGSC), where studies have shown that ~50% of HGSC have abnormalities of DNA repair through BRCA germline and somatic mutation, post-translational changes of BRCA, and abnormalities of other DNA repair molecules. In addition, as aberrant DNA pathways in other histological subtypes of ovarian cancer are identified, and through the combination of PARP inhibitors with other biologic agents, the pool of eligible patients who may benefit from PARP inhibitors will likely expand. Pending review by the Food and Drug Administration (FDA) and the outcome of confirmatory phase III studies, PARP inhibitors could become the first FDA-approved biologic agent for ovarian cancer and also the first new FDA-approval in ovarian cancer since carboplatin and gemcitabine were approved for platinum sensitive ovarian cancer in 2006. This review discusses the PARP inhibitors that are currently in testing for ovarian cancer treatment and the future of this class of anti-cancer agents.

Related: BRCA2 Ovarian Cancer

Flugelman A, Rennert G, Eidelman S
[Psychological and familial aspects of the familial breast and ovarian cancer genetic counseling process].
Harefuah. 2014; 153(1):22-6, 65 [PubMed] Related Publications
Breast cancer is the most prevalent malignancy among women, whilst ovarian cancer is less common but carries a graver prognosis. Carriers of the BRCA mutations have a few-fold higher risk for those diseases. Genetic counseling for the families at risk has been available for almost two decades, since the definition of the mutation. The existence of the deleterious mutation has implications beyond the individual level and touches the lives and future of many other family members. Being part of a BRCA family has medical as well as psychosocial implications. Various barriers and facilitators must be dealt with during the process of sharing the information with kins. Most families cope well with those issues, while some require the guidance of professionals. Special subpopulations, i.e. non-carrier women in BRCA families, young carriers and men who are under minimal personal threat but might transfer the mutation to their off springs, have special needs which should be addressed. The desired outcome of the counseling process is achievement of normal adaptation which balances life in the shadow of uncertainty and threat with the ability to lead a normal life. The process of counseling is multidisciplinary, and along with the advances in scientific and medical aspects, the ethical, legal and social implications (ELSI) have also been developed. The professional personnel escorting those families need to develop and maintain specific skills.

Related: Breast Cancer Ovarian Cancer

Basu NN, Barr L, Evans DG, Ross GL
Threshold for genetic testing in women with breast cancer needs to be determined.
BMJ. 2014; 348:g1863 [PubMed] Related Publications

Related: Breast Cancer

Pei R, Wang P, Zhou Y, et al.
Association of BRCA1 K1183R polymorphism with survival in BRCA1/2-negative chinese familial breast cancer.
Clin Lab. 2014; 60(1):47-53 [PubMed] Related Publications
BACKGROUND: To determine whether a common BRCA1 K1183R polymorphism (3667A > G) affects survival in BRCA1/2-negative Chinese familial breast cancer. We investigated the associations between the BRCA1 E1183R polymorphism and disease-free survival and clinicopathological characteristics in a cohort of 325 Chinese familial breast cancer patients without BRCA1/2 germline mutations.
METHODS: K1183R polymorphism was detected by polymerase chain reaction (PCR)-sequencing assay.
RESULTS: Among the 325 Chinese familial breast cancer patients, the frequencies of the genotypes of E1183R polymorphism were 81.5% for wild-type (AA), 14.5% for heterozygote (AG), and 4.0% for variant (GG). No significant association between the genotypes and clinicopathological characteristics was found. There was a trend association that patients with the AA genotype had a better disease-free survival than those with the AG/GG genotype in univariate analysis (p = 0.111), but patients with AA genotype had a significantly better disease-free survival than did patients with AG or GG genotype in the HER2 positive subgroup (p = 0.012).
CONCLUSIONS: The present study suggests that the AA genotype of BRCA1 K1183R polymorphism is associated with a favorable survival in HER2 positive familial breast cancer patients.

Related: Breast Cancer BRCA2 Polymorphisms

Printz C
Oophorectomy can reduce ovarian cancer risk in women with BRCA mutations: patients benefit from counseling, support.
Cancer. 2013; 119(22):3897-8 [PubMed] Related Publications

Holman LL, Friedman S, Daniels MS, et al.
Acceptability of prophylactic salpingectomy with delayed oophorectomy as risk-reducing surgery among BRCA mutation carriers.
Gynecol Oncol. 2014; 133(2):283-6 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
OBJECTIVE: Given the emerging evidence for the fimbria as the site of origin for many serous carcinomas in BRCA mutation carriers, consideration is being given in studying prophylactic salpingectomy with delayed oophorectomy (PSDO) as a risk-reducing surgery. We aimed to determine the interest in a study of PSDO among these women.
METHODS: We evaluated the results of an online survey conducted by Facing Our Risk of Cancer Empowered (FORCE), a patient advocacy group, from October 2010 to August 2012. Premenopausal BRCA mutation carriers with no history of ovarian cancer or prior bilateral salpingo-oophorectomy (BSO) were included.
RESULTS: Of the 204 women meeting inclusion criteria, median age was 35 years, 92.5% were white, 25.7% were Jewish, and 16.7% had a history of breast cancer. Overall, 34.3% reported interest in a study of salpingectomy, 35.3% were unsure, and 30.4% were not interested in the study. Women noted the possibility of lowering ovarian cancer risk without menopause as a compelling reason to participate (83.8%). Reasons for not participating in a salpingectomy study included surgical complications (46.6%), potential ovarian damage (42.2%), planning BSO soon (32.4%), and surgical costs (32.8%). Acceptable study risks included the need for two surgeries (77.2%), possibility of not lowering ovarian cancer risk (68%), and disruption of ovarian blood supply (66.5%).
CONCLUSIONS: One-third of BRCA mutation carriers indicated definite interest in a PSDO study. Potential study risks were acceptable to most women. These findings suggest that patient accrual for a clinical trial of prophylactic salpingectomy with delayed oophorectomy is possible.

Related: BRCA2 Ovarian Cancer

Vincent-Salomon A
[Triple-negative breast cancer].
Rev Prat. 2013; 63(10):1391-2 [PubMed] Related Publications

Finch AP, Lubinski J, Møller P, et al.
Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation.
J Clin Oncol. 2014; 32(15):1547-53 [PubMed] Article available free on PMC after 20/05/2015 Related Publications
PURPOSE: The purposes of this study were to estimate the reduction in risk of ovarian, fallopian tube, or peritoneal cancer in women with a BRCA1 or BRCA2 mutation after oophorectomy, by age of oophorectomy; to estimate the impact of prophylactic oophorectomy on all-cause mortality; and to estimate 5-year survival associated with clinically detected ovarian, occult, and peritoneal cancers diagnosed in the cohort.
PATIENTS AND METHODS: Women with a BRCA1 or BRCA2 mutation were identified from an international registry; 5,783 women completed a baseline questionnaire and ≥ one follow-up questionnaires. Women were observed until either diagnosis of ovarian, fallopian tube, or peritoneal cancer, death, or date of most recent follow-up. Hazard ratios (HRs) for cancer incidence and all-cause mortality associated with oophorectomy were evaluated using time-dependent survival analyses.
RESULTS: After an average follow-up period of 5.6 years, 186 women developed either ovarian (n = 132), fallopian (n = 22), or peritoneal (n = 32) cancer, of whom 68 have died. HR for ovarian, fallopian, or peritoneal cancer associated with bilateral oophorectomy was 0.20 (95% CI, 0.13 to 0.30; P < .001). Among women who had no history of cancer at baseline, HR for all-cause mortality to age 70 years associated with an oophorectomy was 0.23 (95% CI, 0.13 to 0.39; P < .001).
CONCLUSION: Preventive oophorectomy was associated with an 80% reduction in the risk of ovarian, fallopian tube, or peritoneal cancer in BRCA1 or BRCA2 carriers and a 77% reduction in all-cause mortality.

Related: Fallopian Tube Cancer Ovarian Cancer

Floquet A, Stoeckle E, Croce S, et al.
[Hereditary ovarian carcinomas: clinico-biological features and treatment].
Bull Cancer. 2014; 101(2):167-74 [PubMed] Related Publications
Hereditary ovarian cancers account for 10% of all cases. Two major syndromes with dominant autosomal transmission are identified. The most common one is breast-ovarian cancer syndrome due to BRCA1 and BRCA2 genes mutations, and the Lynch syndrome with mutated MMR genes is the other. Alterations in homologous recombination specifically observed in ovarian cancer with BRCA defects associated to Parp inhibition create a synthetic lethality of special interest. Numerous studies are in progress to explore this promising new approach. Furthermore, it seems that carcinogenesis of these two syndromes are different, suggesting alternative therapeutic options in the near future in order to improve prognosis of ovarian carcinomas.

Related: BRCA2 Ovarian Cancer

Joshi PM, Sutor SL, Huntoon CJ, Karnitz LM
Ovarian cancer-associated mutations disable catalytic activity of CDK12, a kinase that promotes homologous recombination repair and resistance to cisplatin and poly(ADP-ribose) polymerase inhibitors.
J Biol Chem. 2014; 289(13):9247-53 [PubMed] Article available free on PMC after 28/03/2015 Related Publications
Mutations in the tumor suppressors BRCA1 and BRCA2, which encode proteins that are key participants in homologous recombination (HR) repair, occur in ∼20% of high grade serous ovarian cancers. Although only 20% of these tumors have mutations in BRCA1 and BRCA2, nearly 50% of these tumors have defects in HR. Notably, however, the underlying genetic defects that give rise to HR defects in the absence of BRCA1 and BRCA2 mutations have not been fully elucidated. Here we show that the recurrent somatic CDK12 mutations identified in ovarian cancers impair the catalytic activity of this kinase, which is involved in the transcription of a subset of genes, including BRCA1 and other DNA repair genes. Furthermore, we show that disabling CDK12 function in ovarian cancer cells reduces BRCA1 levels, disrupts HR repair, and sensitizes these cells to the cross-linking agents melphalan and cisplatin and to the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888). Taken together, these findings suggest that many CDK12 mutations are an unrecognized cause of HR defects in ovarian cancers.

Related: Cisplatin Ovarian Cancer CDK12 gene

Oktay K, Moy F, Titus S, et al.
Age-related decline in DNA repair function explains diminished ovarian reserve, earlier menopause, and possible oocyte vulnerability to chemotherapy in women with BRCA mutations.
J Clin Oncol. 2014; 32(10):1093-4 [PubMed] Related Publications

Chen S, Wang G, Niu X, et al.
Combination of AZD2281 (Olaparib) and GX15-070 (Obatoclax) results in synergistic antitumor activities in preclinical models of pancreatic cancer.
Cancer Lett. 2014; 348(1-2):20-8 [PubMed] Related Publications
In this study, we explored the antitumor activities of the PARP inhibitor AZD2281 (Olaparib) and the pan-Bcl-2 inhibitor GX15-070 (Obatoclax) in six pancreatic cancer cell lines. While both agents were able to cause growth arrest and limited apoptosis, the combination of the two was able to synergistically cause growth arrest and non-apoptotic cell death. Furthermore, in an in vivo xenograft model, the combination caused substantially increased tumor necrosis compared to either treatment alone. Our results support further investigation of the combination of Bcl-2 and PARP inhibitors for the treatment of pancreatic cancer.

Related: Apoptosis Cancer of the Pancreas Pancreatic Cancer

Powell CB
Risk reducing salpingo-oophorectomy for BRCA mutation carriers: twenty years later.
Gynecol Oncol. 2014; 132(2):261-3 [PubMed] Related Publications


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