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

Gene Summary

Gene:BRCA1; breast cancer 1, early onset
Aliases: IRIS, PSCP, BRCAI, BRCC1, PNCA4, RNF53, BROVCA1, PPP1R53
Location:17q21
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
HPRD
Source:NCBI
Updated:08 March, 2014

Gene
Ontology:

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

Pathways:

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 08 March 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 08 March, 2014 using data from PubMed, MeSH and CancerIndex

Notable

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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BRCA1 and Ovarian Cancer

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BRCA1 and Cancer Screening

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BRCA1 and Prostate Cancer

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Prophylactic Treatments for Women with BRCA1/BRAC2 mutations Therapy

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BRCA1 mutations in Fallopian Tube Cancer

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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.
Related Publications (118)

Genetic Counseling for people with BRAC1/BRCA2 mutations

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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.
Related Publications (131)

Related Links

Latest Publications: BRCA1 (cancer-related)

Metcalfe K, Gershman S, Ghadirian P, et al.
Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis.
BMJ. 2014; 348:g226 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To compare the survival rates of women with BRCA associated breast cancer who did and did not undergo mastectomy of the contralateral breast.
DESIGN: Retrospective analysis.
SETTING: 12 cancer genetics clinics.
PARTICIPANTS: 390 women with a family history of stage I or II breast cancer who were carriers of BRCA1 and BRCA2 mutations and initially treated with unilateral or bilateral mastectomy. 181 patients had mastectomy of the contralateral breast. Patients were followed for up to 20 years from diagnosis.
MAIN OUTCOME MEASURE: Death from breast cancer.
RESULTS: 79 women died of breast cancer in the follow-up period (18 in the bilateral mastectomy group and 61 in the unilateral mastectomy group). The median follow-up time was 14.3 years (range 0.1-20.0 years). At 20 years the survival rate for women who had mastectomy of the contralateral breast was 88% (95% confidence interval 83% to 93%) and for those who did not was 66% (59% to 73%). In a multivariable analysis, controlling for age at diagnosis, year of diagnosis, treatment, and other prognostic features, contralateral mastectomy was associated with a 48% reduction in death from breast cancer (hazard ratio 0.52, 95% confidence interval 0.29 to 0.93; P=0.03). In a propensity score adjusted analysis of 79 matched pairs, the association was not significant (0.60, 0.34 to 1.06; P=0.08). Based on these results, we predict that of 100 women treated with contralateral mastectomy, 87 will be alive at 20 years compared with 66 of 100 women treated with unilateral mastectomy.
CONCLUSIONS: This study suggests that women who are positive for BRCA mutations and who are treated for stage I or II breast cancer with bilateral mastectomy are less likely to die from breast cancer than women who are treated with unilateral mastectomy. Given the small number of events in this cohort, further research is required to confirm these findings.

Related: Breast Cancer Canada USA


Michels KB
Contralateral mastectomy for women with hereditary breast cancer.
BMJ. 2014; 348:g1379 [PubMed] Related Publications


Related: Breast Cancer


Green RC, Farahany NA
Regulation: The FDA is overcautious on consumer genomics.
Nature. 2014; 505(7483):286-7 [PubMed] Related Publications


Related: USA


Mulligan JM, Hill LA, Deharo S, et al.
Identification and validation of an anthracycline/cyclophosphamide-based chemotherapy response assay in breast cancer.
J Natl Cancer Inst. 2014; 106(1):djt335 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: There is no method routinely used to predict response to anthracycline and cyclophosphamide-based chemotherapy in the clinic; therefore patients often receive treatment for breast cancer with no benefit. Loss of the Fanconi anemia/BRCA (FA/BRCA) DNA damage response (DDR) pathway occurs in approximately 25% of breast cancer patients through several mechanisms and results in sensitization to DNA-damaging agents. The aim of this study was to develop an assay to detect DDR-deficient tumors associated with loss of the FA/BRCA pathway, for the purpose of treatment selection.
METHODS: DNA microarray data from 21 FA patients and 11 control subjects were analyzed to identify genetic processes associated with a deficiency in DDR. Unsupervised hierarchical clustering was then performed using 60 BRCA1/2 mutant and 47 sporadic tumor samples, and a molecular subgroup was identified that was defined by the molecular processes represented within FA patients. A 44-gene microarray-based assay (the DDR deficiency assay) was developed to prospectively identify this subgroup from formalin-fixed, paraffin-embedded samples. All statistical tests were two-sided.
RESULTS: In a publicly available independent cohort of 203 patients, the assay predicted complete pathologic response vs residual disease after neoadjuvant DNA-damaging chemotherapy (5-fluorouracil, anthracycline, and cyclophosphamide) with an odds ratio of 3.96 (95% confidence interval [Cl] =1.67 to 9.41; P = .002). In a new independent cohort of 191 breast cancer patients treated with adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, a positive assay result predicted 5-year relapse-free survival with a hazard ratio of 0.37 (95% Cl = 0.15 to 0.88; P = .03) compared with the assay negative population.
CONCLUSIONS: A formalin-fixed, paraffin-embedded tissue-based assay has been developed and independently validated as a predictor of response and prognosis after anthracycline/cyclophosphamide-based chemotherapy in the neoadjuvant and adjuvant settings. These findings warrant further validation in a prospective clinical study.

Related: Breast Cancer Cyclophosphamide Epirubicin Fanconi Anaemia Fanconi Anemia - Molecular Biology Fluorouracil


Weisenberger DJ
Characterizing DNA methylation alterations from The Cancer Genome Atlas.
J Clin Invest. 2014; 124(1):17-23 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
The Cancer Genome Atlas (TCGA) Research Network is an ambitious multi-institutional consortium effort aimed at characterizing sequence, copy number, gene (mRNA) expression, microRNA expression, and DNA methylation alterations in 30 cancer types. TCGA data have become an extraordinary resource for basic, translational, and clinical researchers and have the potential to shape cancer diagnostic and treatment strategies. DNA methylation changes are integral to all aspects of cancer genomics and have been shown to have important associations with gene expression, sequence, and copy number changes. This Review highlights the knowledge gained from DNA methylation alterations in human cancers from TCGA.

Related: Cancer Prevention and Risk Reduction


Leidy J, Khan A, Kandil D
Basal-like breast cancer: update on clinicopathologic, immunohistochemical, and molecular features.
Arch Pathol Lab Med. 2014; 138(1):37-43 [PubMed] Related Publications
CONTEXT: Basal-like breast carcinoma (BLBC) is a distinct molecular subtype of breast carcinoma identified through gene expression profiling studies.
OBJECTIVE: To provide the clinical background, the histologic profile, and the immunohistochemical profile of these tumors and discuss the current knowledge of their molecular signature and their implications on targeted molecular therapy.
DATA SOURCES: Data were obtained from review of the pertinent peer-reviewed literature.
CONCLUSIONS: Basal-like breast carcinomas are aggressive tumors with poor prognosis. Lack of targeted therapy makes their treatment a challenging task. Traditional chemotherapy is still associated with a high risk of relapse and death in a high percentage of patients. Platinum-based chemotherapy has been considered as a candidate for the treatment of BLBCs owing to their BRCA1 phenotype. Approximately 22% of patients treated with single-agent cisplatin show pathologic complete response, which is a comparable rate to that seen with nonplatinum agents. Antiangiogenic agents have been promising, but their currently demonstrated limited response is considered disappointing. Additionally, epidermal growth factor receptor was not shown to be a helpful target for BLBC. A recent study has shown that BLBC appears to be especially sensitive to MEK inhibitors, making it a promising therapeutic possibility. The list of new targets is still evolving and the "magic" therapeutic target is yet to be discovered.

Related: Breast Cancer


Perets R, Wyant GA, Muto KW, et al.
Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca;Tp53;Pten models.
Cancer Cell. 2013; 24(6):751-65 [PubMed] Article available free on PMC after 09/12/2014 Related Publications
High-grade serous ovarian carcinoma presents significant clinical and therapeutic challenges. Although the traditional model of carcinogenesis has focused on the ovary as a tumor initiation site, recent studies suggest that there may be additional sites of origin outside the ovary, namely the secretory cells of the fallopian tube. Our study demonstrates that high-grade serous tumors can originate in fallopian tubal secretory epithelial cells and also establishes serous tubal intraepithelial carcinoma as the precursor lesion to high-grade serous ovarian and peritoneal carcinomas in animal models targeting the Brca, Tp53, and Pten genes. These findings offer an avenue to address clinically important questions that are critical for cancer prevention and early detection in women carrying BRCA1 and BRCA2 mutations.

Related: Fallopian Tube Cancer BRCA2 Ovarian Cancer PTEN


Howard-McNatt M
Pros and cons of screening for BRCA mutations.
N C Med J. 2013 Nov-Dec; 74(6):489-90 [PubMed] Related Publications


Schmidt C
Honing the health message on BRCA mutations.
J Natl Cancer Inst. 2013; 105(24):1843-4 [PubMed] Related Publications


Badora A, Kaleta B, Nowara E, et al.
[Multiple primary malignancies in BRCA1 mutation carriers--two clinical cases].
Ginekol Pol. 2013; 84(10):892-6 [PubMed] Related Publications
Mutations of BRCA1 and BRCA2 genes account for the majority of hereditary breast and ovarian cancers. So far; risk-reducing salpingo-oophorectomy has been the most effective strategy for gynecological cancer prevention in susceptibility gene mutation carriers. It does not prevent, however from the occurrence of primary peritoneal cancer We present two clinical cases of patients with the BRCA1 gene mutation. Both patients had a family history of cancer and both were presenting with metachronic malignances. The first patient, whose mother suffered from breast and ovarian cancer, was diagnosed with left breast cancer in 2004. The patient was 44 years old at diagnosis. Genetic testing revealed the BRCA1 gene mutation. A breast conserving therapy (BCT) was conducted, followed by chemotherapy, radiotherapy and immunotherapy with trastuzumab due to HER2 overexpression. Due to BRCA1 mutation, in November 2005, prophylactic hysterectomy with appendages was performed. Histological examination revealed bilateral ovarian cancer (adenocarcinoma G3) with metastasis to the paraaortal lymph node. The patient received six cycles of chemotherapy: paclitaxel and carboplatin. Ovarian cancer relapsed 3 years later After that the patient received 5 lines of chemotherapy and finally died due to disease progression in September 2011. The second patient, a 49-year-old woman, was diagnosed with breast cancer in July 2003 and subsequently treated with neoadjuvant chemotherapy breast conserving surgery and radiotherapy Genetic testing was also performed and revealed the BRCA1 gene mutation. A year earlier the patient had undergone hysterectomy with appendages due to uterine myomas. Three of her five sisters suffered from breast and ovarian cancer The patients father died of colorectal cancer The patient remained under surveillance. Because of the increasing level of Ca-125 (since October 2004), PET-CT was performed and revealed a tumor lesion of the peritoneum. Histological examination from the biopsy confirmed primary peritoneal cancer (papillary serous adenocarcinoma--primary peritoneal carcinoma). Reexamination of the tissues from hysterectomy with appendages was also performed and revealed an adenocarcinoma in the right ovary Pathologic examination excluded metastasis of a breast cancer Pathomorphology of the ovarian lesion was also different than in the lesions of the peritoneum. Thus, three different tumor types (breast, ovarian and peritoneal cancer) coexisted independently The patient received chemotherapy: paclitaxel and cisplatin. Later on, due to disease progression she was treated with five consecutive chemotherapy regimens and hormonal therapy The patient died in January 2008. These case illustrate that genetic diagnosis may be critical for the overall treatment plan.

Related: Breast Cancer Ovarian Cancer


Moutinho C, Martinez-Cardús A, Santos C, et al.
Epigenetic inactivation of the BRCA1 interactor SRBC and resistance to oxaliplatin in colorectal cancer.
J Natl Cancer Inst. 2014; 106(1):djt322 [PubMed] Article available free on PMC after 09/12/2014 Related Publications
BACKGROUND: A major problem in cancer chemotherapy is the existence of primary resistance and/or the acquisition of secondary resistance. Many cellular defects contribute to chemoresistance, but epigenetic changes can also be a cause.
METHODS: A DNA methylation microarray was used to identify epigenetic differences in oxaliplatin-sensitive and -resistant colorectal cancer cells. The candidate gene SRBC was validated by single-locus DNA methylation and expression techniques. Transfection and short hairpin experiments were used to assess oxaliplatin sensitivity. Progression-free survival (PFS) and overall survival (OS) in metastasic colorectal cancer patients were explored with Kaplan-Meier and Cox regression analyses. All statistical tests were two-sided.
RESULTS: We found that oxaliplatin resistance in colorectal cancer cells depends on the DNA methylation-associated inactivation of the BRCA1 interactor SRBC gene. SRBC overexpression or depletion gives rise to sensitivity or resistance to oxaliplatin, respectively. SRBC epigenetic inactivation occurred in primary tumors from a discovery cohort of colorectal cancer patients (29.8%; n = 39 of 131), where it predicted shorter PFS (hazard ratio [HR] = 1.83; 95% confidence interval [CI] = 1.15 to 2.92; log-rank P = .01), particularly in oxaliplatin-treated case subjects for which metastasis surgery was not indicated (HR = 1.96; 95% CI = 1.13 to 3.40; log-rank P = .01). In a validation cohort of unresectable colorectal tumors treated with oxaliplatin (n = 58), SRBC hypermethylation was also associated with shorter PFS (HR = 1.90; 95% CI = 1.01 to 3.60; log-rank P = .045).
CONCLUSIONS: These results provide a basis for future clinical studies to validate SRBC hypermethylation as a predictive marker for oxaliplatin resistance in colorectal cancer.

Related: Colorectal (Bowel) Cancer Fluorouracil Oxaliplatin Capecitabine


Akbari MR, Lepage P, Rosen B, et al.
PPM1D mutations in circulating white blood cells and the risk for ovarian cancer.
J Natl Cancer Inst. 2014; 106(1):djt323 [PubMed] Related Publications
We compared the frequency of PPM1D mutation in the white blood cells from 1295 ovarian cancer case patients and 834 control subjects. We found a truncating mutation in 20 case patients vs 1 control subject (odds ratio [OR] = 13.07; 95% confidence interval [CI] = 1.75 to 97.55; P < .001). The 12-year mortality of the PPM1D-positive case patients was higher than that of the PPM1D-negative case patients (hazard ratio = 2.02; 95% CI = 1.21 to 3.39; P = .007). Three of the 20 PPM1D carrier case patients had a past history of breast cancer compared with 29 of 1129 noncarriers (OR = 6.69; 95% CI = 1.86 to 24.11; P = .007). The lifetime risks for breast or ovarian cancer among female first-degree relatives of PPM1D mutation carriers were not increased compared with that of case patients without mutations. These observations suggest PPM1D mutations in the mosaic state predispose women to breast and ovarian cancer in the absence of a family history of cancer.

Related: Breast Cancer Canada Ovarian Cancer


Watanabe S, Watanabe K, Akimov V, et al.
JMJD1C demethylates MDC1 to regulate the RNF8 and BRCA1-mediated chromatin response to DNA breaks.
Nat Struct Mol Biol. 2013; 20(12):1425-33 [PubMed] Related Publications
Chromatin ubiquitylation flanking DNA double-strand breaks (DSBs), mediated by RNF8 and RNF168 ubiquitin ligases, orchestrates a two-branch pathway, recruiting repair factors 53BP1 or the RAP80-BRCA1 complex. We report that human demethylase JMJD1C regulates the RAP80-BRCA1 branch of this DNA-damage response (DDR) pathway. JMJD1C was stabilized by interaction with RNF8, was recruited to DSBs, and was required for local ubiquitylations and recruitment of RAP80-BRCA1 but not 53BP1. JMJD1C bound to RNF8 and MDC1, and demethylated MDC1 at Lys45, thereby promoting MDC1-RNF8 interaction, RNF8-dependent MDC1 ubiquitylation and recruitment of RAP80-BRCA1 to polyubiquitylated MDC1. Furthermore, JMJD1C restricted formation of RAD51 repair foci, and JMJD1C depletion caused resistance to ionizing radiation and PARP inhibitors, phenotypes relevant to aberrant loss of JMJD1C in subsets of breast carcinomas. These findings identify JMJD1C as a DDR component, with implications for genome-integrity maintenance, tumorigenesis and cancer treatment.

Related: Breast Cancer


Collins IM, Milne RL, Weideman PC, et al.
Preventing breast and ovarian cancers in high-risk BRCA1 and BRCA2 mutation carriers.
Med J Aust. 2013; 199(10):680-3 [PubMed] Related Publications
OBJECTIVE: To estimate the prevalence of the use of cancer risk-reducing measures among Australian BRCA1 and BRCA2 mutation carriers.
DESIGN, SETTING AND PARTICIPANTS: Prospective follow-up of female carriers of BRCA1 or BRCA2 mutations who had no personal history of cancer and were enrolled in a multiple-case breast cancer family cohort study (kConFab). Data, including cancer events and uptake of risk-reducing surgery and medication were collected by self-report at cohort entry and 3 yearly thereafter. Surgery was confirmed from pathology and medical records. Women were followed up from enrolment until cancer diagnosis, date of last follow-up, or death. Data were collected from 3 November 1997 to 21 May 2012.
MAIN OUTCOME MEASURES: Uptake of risk-reducing surgery and/or medication.
RESULTS: Of 175 BRCA1 and 150 BRCA2 mutation carriers (median age, 37 years at cohort enrolment), 69 (21%) underwent risk-reducing mastectomy, 125 (38%) underwent risk-reducing bilateral salpingo-oophorectomy and nine (3%) participated in a clinical trial of risk-reducing medication, during 2447 person-years of follow-up (median follow-up, 9 years). Sixty-eight women (21%) reported incident cancers, including 52 breast cancers and nine ovarian cancers (defined in this article as high-grade serous cancers of the ovary, fallopian tube or peritoneum).
CONCLUSIONS: There is considerable scope to increase the uptake of cancer risk-reducing measures in Australian BRCA1 and BRCA2 mutation carriers. These findings should drive (i) future research into the factors contributing to low uptake in Australia and (ii) changes to policy and practice to help better translate genetic knowledge into reductions in cancer incidence.

Related: Australia BRCA2


Gonçalves A, Moretta J, Eisinger F, Bertucci F
[Personalized medicine and breast cancer: anticipatory medicine, prognostic evaluation and therapeutic targeting].
Bull Cancer. 2013; 100(12):1295-310 [PubMed] Related Publications
Breast cancer is now considered as a large collection of distinct biological entities, the management of which is increasingly personalized. Personalized medicine - defined as a medicine, which uses molecular profiles, notably genetic profiles, from patients and/or tumors to tailor therapeutic decisions - is now introduced in the management of breast cancer at any stages: screening and prevention of hereditary forms, prognostic and predictive evaluation of early breast cancer, and, more recently, novel clinical trials in advanced breast cancer, where genetic characterization of tumor tissue based on genomics, including next-generation sequencing tools, is used to drive specific therapeutic targeting.

Related: Breast Cancer BRCA2


Etemadmoghadam D, Weir BA, Au-Yeung G, et al.
Synthetic lethality between CCNE1 amplification and loss of BRCA1.
Proc Natl Acad Sci U S A. 2013; 110(48):19489-94 [PubMed] Article available free on PMC after 09/12/2014 Related Publications
High-grade serous ovarian cancers (HGSCs) are characterized by a high frequency of TP53 mutations, BRCA1/2 inactivation, homologous recombination dysfunction, and widespread copy number changes. Cyclin E1 (CCNE1) gene amplification has been reported to occur independently of BRCA1/2 mutation, and it is associated with primary treatment failure and reduced patient survival. Insensitivity of CCNE1-amplified tumors to platinum cross-linking agents may be partly because of an intact BRCA1/2 pathway. Both BRCA1/2 dysfunction and CCNE1 amplification are known to promote genomic instability and tumor progression. These events may be mutually exclusive, because either change provides a path to tumor development, with no selective advantage to having both mutations. Using data from a genome-wide shRNA synthetic lethal screen, we show that BRCA1 and members of the ubiquitin pathway are selectively required in cancers that harbor CCNE1 amplification. Furthermore, we show specific sensitivity of CCNE1-amplified tumor cells to the proteasome inhibitor bortezomib. These findings provide an explanation for the observed mutual exclusivity of CCNE1 amplification and BRCA1/2 loss in HGSC and suggest a unique therapeutic approach for treatment-resistant CCNE1-amplified tumors.

Related: Ovarian Cancer Bortezomib


Hirasawa A, Masuda K, Akahane T, et al.
Family history and BRCA1/BRCA2 status among Japanese ovarian cancer patients and occult cancer in a BRCA1 mutant case.
Jpn J Clin Oncol. 2014; 44(1):49-56 [PubMed] Related Publications
BACKGROUND: This study aimed to examine family history among Japanese ovarian cancer patients and to investigate the TP53 status of fallopian tube epithelial and ovarian cancer cells in a Japanese BRCA1 mutant case that may be associated with the transformed state in hereditary ovarian cancer.
METHODS: One hundred and two primary ovarian cancer patients were retrospectively evaluated in this cross-sectional study. The family history of cancer was determined in probands. In a BRCA1 mutant case, p53 immunostaining and direct sequencing, followed by laser-capture microdissection, were performed for the fallopian tube, considered the origin of ovarian cancer.
RESULTS: Nine of 102 (8.8%) families were regarded as having hereditary breast-ovarian cancer syndrome, two families (2.0%) were diagnosed with Lynch syndrome and six patients harbored BRCA1 or BRCA2 mutations. One case underwent risk-reductive salpingo-oophorectomy as a BRCA1 mutant carrier was retrospectively diagnosed as occult cancer. Common TP53 mutations were detected in cancer and fallopian tube epithelial cells in the case.
CONCLUSIONS: Here, we integrate family cancer history and histology in ovarian cancer cases as well as TP53 status in a BRCA1 mutant case into a discussion regarding carcinogenesis in a Japanese population. The TP53 status for the BRCA1 mutant case examined here supports the recently proposed theory that ovarian cancer develops because of BRCA1 or BRCA2 inactivation and/or TP53 mutations.

Related: Breast Cancer Cancer of Unknown Primary Ovarian Cancer TP53


Huszno J, Budryk M, Kołosza Z, Nowara E
The influence of BRCA1/BRCA2 mutations on toxicity related to chemotherapy and radiotherapy in early breast cancer patients.
Oncology. 2013; 85(5):278-82 [PubMed] Related Publications
OBJECTIVE: The presence of BRCA gene mutation and low expressions of BRCA proteins are associated with a greater sensitivity of tumor cells to ionizing radiation and to cytostatics damaging the DNA of the cells. The purpose of this study was to estimate the rate of adverse events in BRCA1/2-associated breast cancer patients receiving anthracycline-based chemotherapy compared to patients without mutation. The authors also compared radiotherapy toxicity in these 2 groups.
METHODS: The analysis included 270 early-stage breast cancer patients treated between 2006 and 2012. All patients were examined for the presence of BRCA1/2 mutations.
RESULTS: BRCA mutation was detected in 41 (15%) patients. Toxicity grade 3, especially nausea and vomiting, was observed more often in noncarriers (7 vs. 13%, p = 0.0008). Neutropenia was detected more frequently in patients with BRCA1/2 mutation (32 vs. 10%), but only after 1 cycle of chemotherapy (p = 0.0007). There was increased radiation toxicity in BRCA1/2 patients who underwent mastectomy and neoadjuvant chemotherapy (p = 0.016).
CONCLUSIONS: BRCA1/2 mutation carriers seemed to be more at risk of neutropenia after the first cycle of the treatment. In terms of other side effects, there was a lack of increased toxicity in this group. Mastectomy and neoadjuvant chemotherapy were risk factors for radiation toxicity in mutation carriers.

Related: Breast Cancer


Taneja SS
Re: Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer.
J Urol. 2013; 190(6):2093 [PubMed] Related Publications


Lord CJ, Ashworth A
Mechanisms of resistance to therapies targeting BRCA-mutant cancers.
Nat Med. 2013; 19(11):1381-8 [PubMed] Related Publications
Synthetic lethality provides a potential mechanistic framework for the therapeutic targeting of genetic and functional deficiencies in cancers and is now being explored widely. The first clinical exemplification of synthetic lethality in cancer has been the exploitation of inhibitors of poly-(ADP-ribose) polymerase (PARP) for the treatment of cancers with defects in the BRCA1 or BRCA2 tumor suppressor proteins, which are involved in the repair of DNA damage. Although this approach has shown promise, multiple potential resistance mechanisms have been identified. In this Perspective, we discuss these mechanisms and their relevance to the development of selective therapies for BRCA-deficient cancers.

Related: BRCA2 Cancer Prevention and Risk Reduction


Azvolinsky A
Supreme Court ruling broadens BRCA testing options.
J Natl Cancer Inst. 2013; 105(22):1671-2 [PubMed] Related Publications


Menkiszak J, Chudecka-Głaz A, Gronwald J, et al.
[Characteristics of selected clinical features in BRCA1 mutation carriers affected with breast cancer undergoing preventive female genital tract surgeries].
Ginekol Pol. 2013; 84(9):758-64 [PubMed] Related Publications
AIM: Evaluation of patient age and time of the prophylactic surgery as well as incidence of genital cancers and precancerous states observed in histopathology of the postoperative material from BRCA1 gene mutation carriers previously treated for breast cancer.
MATERIAL AND METHODS: 206 carriers of one of the three most common BRCA1 gene mutations (5382insC, C61G and 4153delA) in the Polish population, who were offered the option of prophylactic salpingo-oophorectomy The study group comprised 85 patients with the diagnosis of breast cancer before gynecological preventive surgery The study group was further divided into two subgroups for more detailed assessment of the tested variables. The first subgroup included 67 patients with breast cancer (unilateral or bilateral synchronous). The second subgroup included 18 patients with bilateral metachronous (the second diagnosis of breast cancer was at least 12 months after the first breast cancer diagnosis). The control group consisted of 121 patients with no cancerous lesions before preventive gynecologic surgery The patients undergoing prophylactic treatment had no prior symptoms in female sexual organ and no changes in the diagnostic tests.
RESULTS: The patients with a history of breast cancer underwent genetic testing and preventive surgery of the genital tract at a significantly later age than controls (respectively p = 0.0003, p = 0.0006). The patients with bilateral metachronous breast cancer underwent preventive surgery significantly earlier (p = 0.03). There was a trend indicating a 2.5 times higher risk of developing ovarian cancer among BRCA1 mutation carriers who had already been diagnosed and treated for breast cancer when compared to women without breast cancer diagnosis. The incidence of other genital cancers and precancerous states in BRCA1 gene mutation carriers with history of breast cancer was not statistically significant as compared to controls. Data on the clinical stage, morphological grade, histological type, age and type of pathology and the type of BRCA1 gene mutation did not show a statistically significant difference between the groups.
CONCLUSIONS: Each patient diagnosed with breast cancer should be strongly recommended a genetic test to reduce adverse consequences resulting from postponing the test and, if applicable, the preventive operation until later in life. Preventive surgery should be considered especially in BRCA1 gene mutation carriers previously treated for breast cancer because of the increased risk of ovarian cancer

Related: Breast Cancer Ovarian Cancer


Sun C, Li N, Yang Z, et al.
miR-9 regulation of BRCA1 and ovarian cancer sensitivity to cisplatin and PARP inhibition.
J Natl Cancer Inst. 2013; 105(22):1750-8 [PubMed] Related Publications
BACKGROUND: Expression of BRCA1 is commonly decreased in sporadic ovarian cancer, and this is associated with platinum sensitivity and favorable prognosis. However, multiple mechanisms underlying low BRCA1 expression are not fully understood.
METHODS: A bioinformatics-driven microRNA (miR) library screening was used to identify miRs that regulate BRCA1 expression. The effects of miR-9 on cisplatin (cDDP) and PARP inhibitor sensitivity were measured in ovarian cancer cells and C13* xenograft mice (n = 6 per group). The roles of miR-9 on prognosis were assessed in a cohort of ovarian cancer patients (n = 113) with Kaplan-Meier and Cox proportional hazards analyses. All statistical tests were two-sided.
RESULTS: Reverse miR library screening revealed that miR-9 reduced the normalized luciferase activity to 60.3% (95% confidence interval [CI] = 52.0% to 68.5%; P < .001). miR-9 bound directly to the 3'-UTR of BRCA1 and downregulated BRCA1 expression in ovarian cancer cells. Treatment with miR-9 agomiR sensitized BRCA1-proficient C13* xenograft tumors to cisplatin and AG014699. In serous ovarian cancer, higher levels of miR-9 were inversely correlated with BRCA1 expression (Spearman rank correlation: R (2) = 0.379; P = .003). Patients with higher levels of miR-9 had better chemotherapy response, platinum sensitivity, and longer progression-free survival (PFS) (high vs low miR-9 expression: median PFS = 26.4 months, 95% CI = 13.8 to 39.0 months vs median PFS = 15.4 months, 95% CI = 6.8 to 23.9 months, P = .01).
CONCLUSIONS: miR-9 mediates the downregulation of BRCA1 and impedes DNA damage repair in ovarian cancer. miR-9 may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells to DNA damage and may impact ovarian cancer therapy.

Related: Cisplatin Ovarian Cancer


Moorman PG, Havrilesky LJ, Gierisch JM, et al.
Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: a systematic review and meta-analysis.
J Clin Oncol. 2013; 31(33):4188-98 [PubMed] Related Publications
PURPOSE: To estimate the risks of ovarian cancer and breast cancer associated with oral contraceptive (OC) use among women at elevated risk owing to mutations in BRCA1/2 or a strong family history.
METHODS: We searched PubMed, Embase, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for studies published 2000 to 2012 that evaluated associations between OC use and breast or ovarian cancer among women who are carriers of a BRCA1/2 mutation or have a family history of breast or ovarian cancer.
RESULTS: From 6,476 unique citations, we identified six studies examining ovarian cancer risk in BRCA1/2 mutation carriers and eight studies examining breast cancer risk in BRCA1/2 mutation carriers. For BRCA1/2 mutation carriers combined, meta-analysis showed an inverse association between OC use and ovarian cancer (odds ratio [OR], 0.58; 95% CI, 0.46 to 0.73) and a nonstatistically significant association with breast cancer (OR, 1.21; 95% CI, 0.93 to 1.58). Findings were similar when examining BRCA1 and BRCA2 mutation carriers separately. Data were inadequate to perform meta-analyses examining duration or timing of use. For women with a family history of ovarian or breast cancer, we identified four studies examining risk for ovarian cancer and three for breast cancer, but differences between studies precluded combining the data for meta-analyses, and no overall pattern could be discerned.
CONCLUSION: Our analyses suggest that associations between ever use of OCs and ovarian and breast cancer among women who are BRCA1 or BRCA2 mutation carriers are similar to those reported for the general population.

Related: Breast Cancer Ovarian Cancer


Jeon HS, Lee YH, Lee SY, et al.
A common polymorphism in pre-microRNA-146a is associated with lung cancer risk in a Korean population.
Gene. 2014; 534(1):66-71 [PubMed] Related Publications
INTRODUCTION: MicroRNAs (miRs) play important roles in the development and progression of human cancers. MiR-146a down-regulates epidermal growth factor receptor and the nuclear factor-κB regulatory kinase interleukin-1 receptor-associated kinase 1 genes that play important roles in lung carcinogenesis. This study was conducted to evaluate the association between rs2910164C>G, a functional polymorphism in the pre-miR-146a, and lung cancer risk.
MATERIAL AND METHODS: The rs2910164C>G genotypes were determined in 1094 patients with lung cancer and 1100 healthy controls who were frequency matched for age and gender.
RESULTS: The rs2910164 CG or GG genotype was associated with a significantly decreased risk for lung cancer compared to that of the CC genotype (adjusted odds ratio=0.80, 95% confidence interval=0.66-0.96, P=0.02). When subjects were stratified according to smoking exposure (never, light and heavy smokers), the effect of the rs2910164C>G genotype on lung cancer risk was significant only in never smokers (adjusted odds ratio=0.66, 95% confidence interval=0.45-0.96, P=0.03, under a dominant model for the C allele) and decreased as smoking exposure level increased (Ptrend<0.001). In line with this result, the level of miR-146a expression in the tumor tissues was significantly higher in the GG genotype than in the CC or CG genotype only in never-smokers (P=0.02).
CONCLUSIONS: These findings suggest that the rs2910164C>G in pre-miR-146a may contribute to genetic susceptibility to lung cancer, and that miR-146a might be involved in lung cancer development.

Related: Lung Cancer


Widschwendter M, Rosenthal AN, Philpott S, et al.
The sex hormone system in carriers of BRCA1/2 mutations: a case-control study.
Lancet Oncol. 2013; 14(12):1226-32 [PubMed] Related Publications
BACKGROUND: Penetrance for breast cancer, ovarian cancer, or both in carriers of BRCA1/BRCA2 mutations is disproportionately high. Sex hormone dysregulation and altered end-organ hormone sensitivity might explain this organ-specific penetrance. We sought to identify differences in hormone regulation between carriers of BRCA1/2 and women who are negative for BRCA1/2 mutations.
METHODS: We assessed endometrial thickness for each menstrual cycle day (as an index of hormone regulation) in 393 scans from 228 women in the UK Familial Ovarian Cancer Screening Study (UK FOCSS) known to carry either mutation and 1573 scans from 754 women known to be negative for the mutations. To quantify differences in endometrial thickness we focused on days 10-14 and days 21-26, and calculated the area under the curve. We then compared serum oestradiol and progesterone titres during these days of the menstrual cycle in the same groups. Follicular and luteal oestradiol and progesterone serum titres were grouped into quartiles and odds ratios were calculated with logistic regression.
FINDINGS: Follicular phase endometrial thickness of carriers of the mutations adjusted for age and day of the menstrual cycle was higher (odds ratio [OR] 1·11, 95% CI 1·03-1·20; p=0·0063) and luteal phase endometrial thickness lower (0·90, 0·83-0·98; p=0·027) than for women negative for the mutations. Median luteal phase titres of progesterone were 121% higher (p=0·00037) in carriers than in women negative for the mutations, and for oestradiol were 33% higher (p=0·007)-ie, 59% of carriers had concentrations of serum progesterone that would have been in the top quartile of concentrations in the control group (OR 8·0, 95% CI 2·1-52·57; p=0·008).
INTERPRETATION: Carriers of BRCA1/BRCA2 mutations are exposed to higher titres of oestradiol and progesterone-known risk-factors for breast cancer. Higher titres of oestradiol in carriers are compatible with this hormone having a role in ovarian carcinogenesis in such women. Our findings could not be explained by differential contraceptive pill use.

Related: Breast Cancer Ovarian Cancer


Hickey M
Untangling BRCA mutations, sex hormones, and cancer risk.
Lancet Oncol. 2013; 14(12):1151-2 [PubMed] Related Publications


Jin J
Women with breast cancer who opt for contralateral prophylactic mastectomy may overestimate future risk.
JAMA. 2013; 310(15):1548 [PubMed] Related Publications


Israelsen WJ, Dayton TL, Davidson SM, et al.
PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells.
Cell. 2013; 155(2):397-409 [PubMed] Article available free on PMC after 10/10/2014 Related Publications
The pyruvate kinase M2 isoform (PKM2) is expressed in cancer and plays a role in regulating anabolic metabolism. To determine whether PKM2 is required for tumor formation or growth, we generated mice with a conditional allele that abolishes PKM2 expression without disrupting PKM1 expression. PKM2 deletion accelerated mammary tumor formation in a Brca1-loss-driven model of breast cancer. PKM2 null tumors displayed heterogeneous PKM1 expression, with PKM1 found in nonproliferating tumor cells and no detectable pyruvate kinase expression in proliferating cells. This suggests that PKM2 is not necessary for tumor cell proliferation and implies that the inactive state of PKM2 is associated with the proliferating cell population within tumors, whereas nonproliferating tumor cells require active pyruvate kinase. Consistent with these findings, variable PKM2 expression and heterozygous PKM2 mutations are found in human tumors. These data suggest that regulation of PKM2 activity supports the different metabolic requirements of proliferating and nonproliferating tumor cells.

Related: Breast Cancer


Khadim MF, Eastwood P, Price J, et al.
Multidisciplinary one-stage risk-reducing gynaecological and breast surgery with immediate reconstruction in BRCA-gene carrier women.
Eur J Surg Oncol. 2013; 39(12):1346-50 [PubMed] Related Publications
Familial breast cancer accounts for 5-10% of all breast cancers. Due to BRCA1/2 tumour suppressor gene mutation, hereditary breast and ovarian syndrome is the most common form. Risk-reducing gynaecological and breast surgery is offered to such patients in ever-increasing numbers. Hence, the development of a multi-specialty combined treatment approach is called for. Twenty-two BRCA gene-mutation carrier women underwent one-stage gynaecological and breast risk-reducing surgery and immediate reconstruction between January 2005 and December 2011 at the Belfast City Hospital. Their mean age was 41.2 years (median 41 years). Nearly half of the patients were BRCA2 and a quarter were BRCA1 carriers. The rest were positive for both genes. Hormone-replacement therapy was initiated in 14 women. Average theatre time and stay in the hospital were three hours and two and a half days, respectively. Two patients developed complications unrelated to combining the procedures. Both were treated conservatively and recovered. The one-stage approach logically proves economical by limiting the time the patients are in the hospital and away from work. We describe our multidisciplinary team service that is offering safe and economical one-stage risk-reducing surgery and reconstruction to young BRCA gene-mutation carrier women in Northern Ireland.

Related: Breast Cancer BRCA2 Ovarian Cancer


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