Gene Summary

Gene:BRCA1; BRCA1, DNA repair associated
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:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:breast cancer type 1 susceptibility protein
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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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 (1992-2017)
Graph generated 11 March 2017 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 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (10)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Ovarian CancerBRCA1 and Ovarian Cancer View Publications3000
Breast CancerBRCA1 mutations in Breast Cancer View Publications3000
-Genetic Counseling for people with BRAC1/BRCA2 mutations View Publications333
Breast Cancer, FamilialProphylactic Treatments for Women with BRCA1/BRAC2 mutations Therapy View Publications260
Prostate CancerBRCA1 and Prostate Cancer View Publications210
Colorectal CancerBRCA1 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.
View Publications153
Cancer ScreeningBRCA1 and Cancer Screening View Publications147
Breast Cancer185delAG 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.
View Publications141
Fallopian tube cancerBRCA1 mutations in Fallopian Tube Cancer View Publications140
Hereditary Breast and Ovarian Cancer SyndromeHereditary 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]
View Publications89

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: BRCA1 (cancer-related)

Chudecka-Głaz A, Cymbaluk-Płoska A, Strojna A, Menkiszak J
HE4 Serum Levels in Patients with BRCA1 Gene Mutation Undergoing Prophylactic Surgery as well as in Other Benign and Malignant Gynecological Diseases.
Dis Markers. 2017; 2017:9792756 [PubMed] Free Access to Full Article Related Publications
Objective. We assess the behavior of serum concentrations of HE4 marker in female carriers of BRCA1 and assess the diagnostic usefulness of HE4 in ovarian and endometrial cancer. Methods. A total of 619 women with BRCA1 gene mutation, ovarian, endometrial, metastatic, other gynecological cancers, or benign gynecological diseases were included. Intergroup comparative analyses were carried out, the BRCA1 gene carriers subgroup was subjected to detailed analysis, and ROC curves were determined for the assessment of diagnostic usefulness of HE4 in ovarian and endometrial cancer. Results. Statistically lower serum HE4 and CA 125 levels were observed in BRCA1 gene mutation premenopausal carriers. Occult ovarian/fallopian tube cancer was found 3.6%. Each of those patients was characterized by slightly elevated levels of either CA 125 (63.9 and 39.4 U/mL) or HE4 (79 pmol/L). The ROC-AUC curves were 0.892 and 0.894 for diagnostic usefulness of ovarian cancer and 0.865 for differentiation of endometrial cancer from endometrial polyps. Conclusions. Patients with BRCA1 gene mutations have relatively low serum HE4 levels. Even the slightest elevation in HE4 or CA 125 levels in female BRCA1 carriers undergoing prophylactic surgery should significantly increase oncological alertness. The HE4 marker is valuable in ovarian and uterine cancer diagnosis.

Kurian AW, Griffith KA, Hamilton AS, et al.
Genetic Testing and Counseling Among Patients With Newly Diagnosed Breast Cancer .
JAMA. 2017; 317(5):531-534 [PubMed] Related Publications

Sander Effron S, Makvandi M, Lin L, et al.
PARP-1 Expression Quantified by [(18)F]FluorThanatrace: A Biomarker of Response to PARP Inhibition Adjuvant to Radiation Therapy.
Cancer Biother Radiopharm. 2017; 32(1):9-15 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
INTRODUCTION: Poly (ADP-ribose) polymerase 1 (PARP-1) is the major target of clinical PARP inhibitors and is a potential predictive biomarker for response to therapy. Due to the limited success of PARP inhibitors as monotherapy, investigators have shifted the clinical role of PARP inhibitors to the adjuvant setting. In this study, we evaluate the radiotracer [(18)F]FluorThanatrace ([(18)F]FTT) as a marker of PARP expression in vitro and the associated biological implications of PARP-1 expression in PARP inhibitor treatment adjuvant to radiation therapy.
MATERIALS AND METHODS: SNU-251 (BRCA1-mutant) and SKOV3 (BRCA1-WT) cell lines were evaluated in vitro by using the radiotracer [(18)F]FTT. Pharmacological binding assays were performed at baseline and were correlated with PARP-1 protein expression measured by Western blot protein analysis. Cell viability and clonogenic assays were used to characterize in vitro cytotoxicity for treatments, including: PARP inhibitors alone, radiation alone, and PARP inhibitor adjuvant to radiation. Western blot protein analysis was used to assess response to treatment by using γH2AX to measure DNA damage and PAR to measure the catalytic inhibition of PARP.
RESULTS: [(18)F]FTT was capable of measuring PARP-1 protein expression in vitro and corresponded to Western blot protein analysis at baseline. The addition of a PARP inhibitor enhanced radiation effects in both cell lines; however, a greater synergy was observed in the SNU-251 cell line that expresses a BRCA1 mutation and homologous recombination deficiency. Western blot protein analysis showed that the addition of a PARP inhibitor adjuvant to radiation increases DNA damage in both cell lines and reduces PARP enzymatic activity as measured by PAR.
CONCLUSIONS: In this work, we found that PARP-1 expression positively corresponds in vitro to the response of PARP inhibitors in combination with radiation therapy in ovarian cancer.

Cao Y, Zhang G, Wang P, et al.
Clinical significance of UGT1A1 polymorphism and expression of ERCC1, BRCA1, TYMS, RRM1, TUBB3, STMN1 and TOP2A in gastric cancer.
BMC Gastroenterol. 2017; 17(1):2 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
BACKGROUND: Individualized therapeutic regimen is a recently intensively pursued approach for targeting diseases, in which the search for biomarkers was considered the first and most important. Thus, the goal of this study was to investigate whether the UGT1A1, ERCC1, BRCA1, TYMS, RRM1, TUBB3, STMN1 and TOP2A genes are underlying biomarkers for gastric cancer, which, to our knowledge, has not been performed.
METHODS: Ninety-eight tissue specimens were collected from gastric cancer patients between May 2012 and March 2015. A multiplex branched DNA liquidchip technology was used for measuring the mRNA expressions of ERCC1, BRCA1, TYMS, RRM1, TUBB3, STMN1 and TOP2A. Direct sequencing was performed for determination of UGT1A1 polymorphisms. Furthermore, correlations between gene expressions, polymorphisms and clinicopathological characteristics were investigated.
RESULTS: The expressions of TYMS, TUBB3 and STMN1 were significantly associated with the clinicopathological characteristics of age, gender and family history of gastric cancer, but not with differentiation, growth patterns, metastasis and TNM staging in patients with gastric cancer. No clinical characteristics were correlated with the expressions of ERCC1, BRCA1, RRM1 and TOP2A. Additionally, patients carrying G allele at -211 of UGT1A1 were predisposed to developing tubular adenocarcinoma, while individuals carrying 6TAA or G allele respectively at *28 or -3156 of UGT1A1 tended to have a local invasion.
CONCLUSIONS: The UGT1A1 polymorphism may be useful to screen the risk population of gastric cancer, while TYMS, TUBB3 and STMN1 may be potential biomarkers for prognosis and chemotherapy guidance.

Tesson S, Richards I, Porter D, et al.
Women's preferences for contralateral prophylactic mastectomy following unilateral breast cancer: What risk-reduction makes it worthwhile?
Breast. 2017; 31:233-240 [PubMed] Related Publications
OBJECTIVES: Contralateral prophylactic mastectomy (CPM) reduces the risk of contralateral breast cancer (BC) following unilateral BC, but may not increase survival in BRCA1/2 mutation negative women. Despite this, and the risk for adverse physical and psychological impact, uptake is increasing in BRCA1/2 mutation negative women. We aimed to quantify the degree of reduction in lifetime contralateral BC risk women required to justify CPM, and to explore demographic, disease and psychosocial predictors of preferences using Protection Motivation Theory (PMT) as a theoretical framework. Reasoning behind preferences was also examined.
MATERIALS AND METHODS: 388 women previously diagnosed with unilateral BC, of negative or unknown BRCA1/2 status, were recruited from an advocacy group research database. Two hypothetical risk trade-off scenarios were used to quantify the reduction in lifetime contralateral BC risk that women judged necessary to justify CPM, using a 5% and 20% baseline. Demographic, disease and PMT measures were assessed using a questionnaire.
RESULTS: Most women required their risk to be more than halved from a 5% or 20% baseline to justify CPM. Polarised preferences were also common, with some women consistently accepting or refusing CPM independent of risk/benefit trade-offs. Preferences were associated with coping self-efficacy and having a prior CPM. Explanations for judging CPM worthwhile included reducing or eliminating contralateral BC risk, attaining breast symmetry and reducing worry.
CONCLUSION: Risk-reduction preferences were highly variable. Decisive factors in women's preferences for CPM related to clinical, psychological and cosmetic outcomes, but not to demographic or disease characteristics.

Dréan A, Lord CJ, Ashworth A
PARP inhibitor combination therapy.
Crit Rev Oncol Hematol. 2016; 108:73-85 [PubMed] Related Publications
In 2014, olaparib (Lynparza) became the first PARP (Poly(ADP-ribose) polymerase) inhibitor to be approved for the treatment of cancer. When used as single agents, PARP inhibitors can selectively target tumour cells with BRCA1 or BRCA2 tumour suppressor gene mutations through synthetic lethality. However, PARP inhibition also shows considerable promise when used together with other therapeutic agents. Here, we summarise both the pre-clinical and clinical evidence for the utility of such combinations and discuss the future prospects and challenges for PARP inhibitor combinatorial therapies.

van Marcke C, De Leener A, Berlière M, et al.
Routine use of gene panel testing in hereditary breast cancer should be performed with caution.
Crit Rev Oncol Hematol. 2016; 108:33-39 [PubMed] Related Publications
Breast cancer is the most frequent cancer occurring in women. Ten percent of these cancers are considered hereditary. Among them, 30% are attributed to germline mutations in the tumor suppressor genes BRCA1 and BRCA2. Other genes of lower penetrance are also known, explaining together up to 40% of the hereditary risk of breast cancer. New techniques, such as next-generation sequencing, allow the simultaneous analysis of multiple genes in a cost-effective way. As a logical consequence, gene panel testing is entering clinical practice with the promise of personalized care. We however advocate that gene panel testing is not ready for non-specialist clinical use, as it generates many variants of unknown significance and includes more genes than are presently considered clinically useful. We hereby review the data for each gene that can change the risk management of patients carrying a pathogenic variant.

Bayraktar S, Arun B
BRCA mutation genetic testing implications in the United States.
Breast. 2017; 31:224-232 [PubMed] Related Publications
BRCA mutation carriers have a very high risk of breast and ovarian cancer by age 70, in the ranges 47%-66% and 40%-57%, respectively. Additionally, women with BRCA mutation-associated breast cancer also have an elevated risk of other or secondary malignancies. Fortunately, the breast and ovarian cancer outcome for BRCA1/2 mutation carriers is at least as good as for non-carriers with chemoprevention, prophylactic surgeries and appropriate use of therapies. Therefore, identification of those who might have a mutation is important so that genetic counseling, testing, screening and prevention strategies can be applied in a timely manner. This article reviews the impact of genetic testing in general, timing of genetic testing after diagnosis and prior knowledge of mutation status in BRCA carriers with newly diagnosed breast cancer. Additionally, risk-reducing surgeries including the prophylactic contralateral mastectomy, and bilateral salpingo-oophorectomy and the sensitivity of BRCA-defective breast cancer cell lines to differential chemotherapeutic agents will be discussed.

Rowland E, Plumridge G, Considine AM, Metcalfe A
Preparing young people for future decision-making about cancer risk in families affected or at risk from hereditary breast cancer: A qualitative interview study.
Eur J Oncol Nurs. 2016; 25:9-15 [PubMed] Related Publications
PURPOSE: Women carrying the mutated BRCA gene, have approximately an 80% life-time risk of developing breast cancer with 50% risk of their children inheriting the gene mutation. Many parents find it difficult to know when and how to disclose this information to their children and how such disclosure might affect their child's future decision-making.
METHOD: This study explored the communication of genetic risk information in families using qualitative semi-structured interviews conducted with parents, children (7-11years) and young people (12-18years) affected or at risk from a BRCA gene mutation. Thematic analysis was applied to coded transcripts producing four themes; family communication, perception of cancer risks, risk management strategies and impact of genetic risk communication in children and young people's decision making.
RESULTS: Twenty-seven individuals from 11 families took part, recruited through purposive sampling techniques. Cancer risk caused by a BRCA gene mutation induced a sense of fear in parents about their children's future. As a result, parents with hereditary breast cancer disclosed limited information about the risks associated with prophylactic surgery and/or the psychological and emotional impacts of surgery on body image. This had implications to children and young people's perceptions of prophylactic procedures, which were already influenced by cultural understandings of the 'desirable body' and increasing acceptance and proliferation cosmetic surgery.
CONCLUSION: Lack of risk management information and the acculturation of cosmetic surgery combined to limit children and young people's understanding of the impact of hereditary breast cancer; reducing their ability to actualise the physiological, psychological and emotional consequences of surgery.

Márquez-Rodas I, Lobo M, Flores-Sanchez C, et al.
Five Years of Multidisciplinary Care in Hereditary Cancer: Our Experience in a Spanish University Hospital.
Oncology. 2017; 92(2):68-74 [PubMed] Related Publications
OBJECTIVE: To analyse the evolution of a multidisciplinary heredofamilial cancer unit (HFCU) in a university hospital.
METHODS: This was a retrospective analysis of the activity of our HFCU in its first 5 years of existence.
RESULTS: Between July 2010 and July 2015, 1,518 patients from 1,318 families attended our HFCU. Genetic testing was offered to 862 patients. Of those, 833 (96.6%) accepted testing, with available results for 636 (76.4%). Pathogenic mutations in BRCA1 and BRCA2 were found in 175 patients. Lynch syndrome and adenomatous polyposis were the most frequent syndromes diagnosed (151/175, 86.3%) among 17 different syndromes studied. Of the 404 patients without a previous genetic diagnosis in the family, 62 (15.3%) were found to have mutations in disease-causing genes. Prophylactic surgery and follow-up (33.7%) or follow-up only (66.3%) was proposed for mutation carriers according to international guidelines and patients' preferences.
CONCLUSION: We have a high mutation detection rate, genetic test acceptance, and compliance with risk reduction strategies. However, there is room for improvement, especially in genetic testing timing, considering that an increase in the indications for genetic testing is expected.

Eatemadi A, Daraee H, Aiyelabegan HT, et al.
Synthesis and Characterization of Chrysin-loaded PCL-PEG-PCL nanoparticle and its effect on breast cancer cell line.
Biomed Pharmacother. 2016; 84:1915-1922 [PubMed] Related Publications
BACKGROUND: Nano-therapy exhibit the potential of revolutionizing cancer therapy. This field introduces nanovectors/nanocarriers for anticancer drugs targeted delivery, and also finds application in imaging. Chrysin, a natural flavonoid, was recently studied as having important biological roles in chemical defenses, nitrogen fixation, anti-inflammatory, and anti-oxidant properties. We aim at studying the effect of nano-chrysin on breast cancer cell line.
METHODS: The effect of chrysin loaded PCL-PEG-PCL was studied on T47D breast cancer cell line. The structure and drug-loading of chrysin were characterized using (1)H NMR, FT-IR and SEM. The in vitro cytotoxicity of pure and nano-chrysin was tested by the MTT assay. Gene expression of FTO, hTERT, and BRCA1 were evaluated using Real-time PCR.
RESULTS: Data analysis from MTT assay showed that chrysin has a time-dependent cytotoxic effect on T47D cell line. Furthermore, the results of Real-time PCR suggested that encapsulated chrysin have higher antitumor effect on gene expression of FTO, BRCA1 and hTERT than free chrysin.
CONCLUSION: Combined nano-chrysin therapy will not only improve cancer cell cytotoxicity, but also be a complementary and potential complex in breast cancer therapy.

Brédart A, Kop JL, De Pauw A, et al.
Effect on perceived control and psychological distress of genetic knowledge in women with breast cancer receiving a BRCA1/2 test result.
Breast. 2017; 31:121-127 [PubMed] Related Publications
Information provision during BRCA1/2 genetic counseling is complex and expected to be increasingly so with gene panel testing. This prospective study evaluated whether genetic knowledge in counselees with breast cancer (BC) after a pre-test genetic counseling visit (T1) enhance their feeling of personal control while minimizing distress after the notification of BRCA1/2 result (T2). At T1, 243 (89% response rate) counselees completed questionnaires on genetic knowledge (BGKQ), perceived cancer genetic risk; of which, at T2, 180 (66%) completed the BGKQ again, scales of anxiety/depression, distress specific to genetic risk, and perceived control. Multilevel models were performed accounting for clinician, and testing an effect of knowledge on psychological outcomes according to the adequacy of counselees' perceived genetic predisposition to cancer. The mean knowledge score was moderate at T1, decreased while not significantly differing by BRCA1/2 test result at T2. Knowledge at T1 had no direct effect on psychological outcomes, but in counselees who over-estimated their cancer genetic risk, higher knowledge at T1 predicted higher specific distress at T2. In BC affected counselees who over-estimate their cancer genetic risk, higher BRCA1/2 pre-test genetic knowledge seem to lead to increased specific distress. Identifying these BC affected counselees who over-estimate their genetic cancer risk and helping them to interpret their genetic knowledge instead of providing them with exhaustive genetic information could minimize their distress after test result receipt.

Egloff H, Jatoi A
Do Ovarian Cancer Patients with a Family History of Cancer (Suspected BRCA1 or BRCA2 Mutation) Suffer Greater Chemotherapy Toxicity?
Cancer Invest. 2016; 34(10):531-535 [PubMed] Related Publications
OBJECTIVE: Few studies have examined toxicity from potentially curative chemotherapy in ovarian cancer patients at risk for breast cancer susceptibility (BRCA) mutation.
METHODS/RESULTS: Ninety-four of the 482 patients appeared at risk for a mutation based on family history and 23 had a confirmed mutation. Hospitalization or emergency department visits were not increased based on family history with odds ratios (95% confidence intervals) of 0.88 (0.52, 1.45) (p =.62) and 0.90 (0.49, 1.58) (p =.71), respectively; similar findings were observed with confirmed mutations. Trends favored improved survival.
CONCLUSIONS: Concern for a BRCA mutation should not preclude full dose chemotherapy in ovarian cancer patients treated with curative intent.

Zolot J
New Advisory on Contralateral Prophylactic Mastectomy.
Am J Nurs. 2016; 116(11):17 [PubMed] Related Publications
Breast surgeons recommend against the procedure unless cancer risk is increased.

Wang P, Ma D, Wang J, et al.
INPP4B-mediated DNA repair pathway confers resistance to chemotherapy in acute myeloid leukemia.
Tumour Biol. 2016; 37(9):12513-12523 [PubMed] Related Publications
INPP4B has been recently shown to be a poor prognostic marker and confer chemo- or radio-resistance in AML cells, whereas, the underlying mechanisms remain unclear. Herein, we aimed to explore the possible mechanisms mediated the resistance to chemotherapy in AML. We found that INPP4B-mediated resistance to genotoxic drug, cytarabine, was accompanied by lower p-H2AX accumulation in KG-1 cells, and INPP4B knockdown evidently sensitized KG-1 cells to cytarabine, meanwhile, p-H2AX expression was increased dramatically. Then, we observed that INPP4B knockdown inhibited the loss of p-H2AX expression after cytarabine removal in INPP4B-silenced KG-1 cells, whereas, in control KG-1 cells, the expression of p-H2AX was reduced in a time-dependent manner. Next, INPP4B knockdown can significantly downregulate ATM expression and subsequently inhibit the activation of ATM downstream targets of p-ATM, p-BRCA1, p-ATR, and p-RAD51. Furthermore, nuclear localization of p65 was inhibited after INPP4B knockdown, and reactivation of p65 can rescue the INPP4B knockdown-induced inhibition of ATM, p-ATM, p-BRCA1, p-ATR, and p-RAD51. Finally, INPP4B expression was positively correlated with ATM expression in AML cells, both INPP4B knockdown and KU55933 can significantly sensitize primary myeloid leukemic cells to cytarabine treatment.Collectively, these data suggest that enhanced ATM-dependent DNA repair is involved in resistance to chemotherapy in INPP4B(high) AML, which could be mediated by p65 nuclear translocation, combination chemotherapy with INPP4B or DNA repair pathway inhibition represents a promising strategy in INPP4B(high) AML.

Dimitrova D, Ruscito I, Olek S, et al.
Germline mutations of BRCA1 gene exon 11 are not associated with platinum response neither with survival advantage in patients with primary ovarian cancer: understanding the clinical importance of one of the biggest human exons. A study of the Tumor Bank Ovarian Cancer (TOC) Consortium.
Tumour Biol. 2016; 37(9):12329-12337 [PubMed] Related Publications
Germline mutations in BRCA1 gene have been reported in up to 20 % of epithelial ovarian cancer (EOC) patients. Distinct clinical characteristics have been attributed to this special EOC population. We hypothesized that mutations in different BRCA1 gene exons may differently affect the clinical course of the disease. The aim of this study was to analyze, in a large cohort of primary EOCs, the clinical impact of mutations in BRCA1 gene exon 11, the largest exon of the gene sequence encoding the 60 % of BRCA1 protein. Two hundred sixty-three primary EOC patients, treated between 2000 and 2008 at Charité University Hospital of Berlin, were included. Patients' blood samples were obtained from the Tumor Ovarian Cancer (TOC) Network ( ). Direct sequencing of BRCA1 gene exon 11 was performed for each patient to detect mutations. Based on their BRCA1 exon 11 mutational status, patients were compared regarding clinico-pathological variables and survival. Mutations in BRCA1 exon 11 were found in 18 out of 263 patients (6.8 %). Further 10/263 (3.8 %) cases showed variants of uncertain significance (VUS). All exon 11 BRCA1-positive tumors (100 %) were Type 2 ovarian carcinomas (p = 0.05). Age at diagnosis was significantly younger in Type 2 exon 11 mutated patients (p = 0.01). On multivariate analysis, BRCA1 exon 11 mutational status was not found to be an independent predictive factor for optimal cytoreduction, platinum response, or survival. Mutations in BRCA1 gene exon 11 seem to predispose women to exclusively develop a Type 2 ovarian cancer at younger age. Exon 11 BRCA1-mutated EOC patients showed distinct clinico-pathological features but similar clinical outcome with respect to sporadic EOC patients.

Monk BJ, Lorusso D, Italiano A, et al.
Trabectedin as a chemotherapy option for patients with BRCA deficiency.
Cancer Treat Rev. 2016; 50:175-182 [PubMed] Related Publications
Trabectedin is a marine-derived product that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata and the first anticancer marine drug to be approved by the European Union. It is currently used as a single agent for the treatment of patients with soft tissue sarcoma after failure of anthracyclines and ifosfamide, or for those patients who are unsuited to receive these agents, and in patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. Trabectedin has a unique multi-faceted mechanism of action that involves transcription regulation and DNA repair systems, including transcription-coupled nucleotide excision repair and homologous recombination repair (HRR) as the main hallmarks of its antiproliferative activity. In addition, trabectedin has shown the ability to modulate the tumor microenvironment. Indeed, the activity of trabectedin is related to altered function and expression of DNA repair genes, such as BRCA1 (BReast-CAncer susceptibility gene 1) and BRCA2. The particular sensitivity of sarcoma, ovarian and breast cancer cells deficient in HRR, previously observed in preclinical models, now has been confirmed in the clinical setting as well, suggesting that BRCA mutations are associated with improved clinical responses to trabectedin. Current efforts are focused on the evaluation of these unique features of trabectedin and on the identification of predictive factors for patients with an objective to determine whether a deficiency of HRR DNA repair pathway could impact the clinical benefit achieved from trabectedin.

Larouche G, Chiquette J, Plante M, et al.
Usefulness of Canadian Public Health Insurance Administrative Databases to Assess Breast and Ovarian Cancer Screening Imaging Technologies for BRCA1/2 Mutation Carriers.
Can Assoc Radiol J. 2016; 67(4):308-312 [PubMed] Related Publications
PURPOSE: In Canada, recommendations for clinical management of hereditary breast and ovarian cancer among individuals carrying a deleterious BRCA1 or BRCA2 mutation have been available since 2007. Eight years later, very little is known about the uptake of screening and risk-reduction measures in this population. Because Canada's public health care system falls under provincial jurisdictions, using provincial health care administrative databases appears a valuable option to assess management of BRCA1/2 mutation carriers. The objective was to explore the usefulness of public health insurance administrative databases in British Columbia, Ontario, and Quebec to assess management after BRCA1/2 genetic testing.
METHODS: Official public health insurance documents were considered potentially useful if they had specific procedure codes, and pertained to procedures performed in the public and private health care systems.
RESULTS: All 3 administrative databases have specific procedures codes for mammography and breast ultrasounds. Only Quebec and Ontario have a specific procedure code for breast magnetic resonance imaging. It is impossible to assess, on an individual basis, the frequency of others screening exams, with the exception of CA-125 testing in British Columbia. Screenings done in private practice are excluded from the administrative databases unless covered by special agreements for reimbursement, such as all breast imaging exams in Ontario and mammograms in British Columbia and Quebec. There are no specific procedure codes for risk-reduction surgeries for breast and ovarian cancer.
CONCLUSION: Population-based assessment of breast and ovarian cancer risk management strategies other than mammographic screening, using only administrative data, is currently challenging in the 3 Canadian provinces studied.

Eftekhari-Sis B, Karaminejad S, Karimi F
A Nano-Biosensor for the Detection of 185delAG Mutation in BRCA1 Gene, Leading to Breast Cancer.
Cancer Invest. 2016; 34(9):431-439 [PubMed] Related Publications
A method was developed for the detection of 185delAG mutation in BRCA1 gene, which is responsible for 85% and 63% lifetime risks of hereditary breast and ovarian cancer in women, respectively. The protocol is based on the quenching and recovering fluorescence emission of fluorescein-based dye (FAM)-labeled DNA in the presence of graphene oxide (GO), followed by addition of cDNA or mDNA. In addition, ligase reaction between a DNA probe attached to GO and a DNA possessing FAM on 5' terminal in the presence of cDNA or mDNA was applied.

Cecener G, Guney Eskiler G, Egeli U, et al.
Association of PALB2 sequence variants with the risk of early-onset breast cancer in patients from Turkey.
Mol Biol Rep. 2016; 43(11):1273-1284 [PubMed] Related Publications
The PALB2 gene, has been accepted as a moderate-penetrance gene associated with breast cancer susceptibility and this gene product is involved in the DNA damage repair pathway via co-localization with BRCA2. Germline PALB2 mutations are associated with an increased breast cancer risk. However, the prevalence of the diverse types of PALB2 variants depend on the population. Thus, the aim of the present study was to determine, for the first time, the prevalence of PALB2 variants in a Turkish population of BRCA1/BRCA2-negative early-onset patients with breast cancer. In total, 223 Turkish patients with BRCA1/BRCA2 negative early-onset breast cancer and 60 unaffected women were included in the study. All the coding exons and intron/exon boundaries of PALB2 were subjected to mutational analysis by heteroduplex analysis (HDA)and DNA sequencing. Eighteen PALB2 variants were found in breast cancer patients within the Turkish population. Three variants (c.271G>A, c.404C>A and c.2981T>A) have not been previously reported. In addition, nine intronic variants were described, and this study is the first to describe the c.1685-44T>A intronic variant. The prevalence of possible pathogenic PALB2 variants was found to be 4.03 % in BRCA1/2-negative Turkish patients with early-onset breast cancer. Different variants of PALB2 have been reported in the literature, and the prevalence of these variants could different for each population. This is the first study to investigate the prevalence of PALB2 variants in Turkish patients with early-onset breast cancer.

Baretta Z, Mocellin S, Goldin E, et al.
Effect of BRCA germline mutations on breast cancer prognosis: A systematic review and meta-analysis.
Medicine (Baltimore). 2016; 95(40):e4975 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
BACKGROUND: The contribution of BRCA germline mutational status to breast cancer patients' prognosis is unclear. We aimed to systematically review and perform meta-analysis of the available evidence of effects of BRCA germline mutations on multiple survival outcomes of breast cancer patients as a whole and in specific subgroups of interest, including those with triple negative breast cancer, those with Ashkenazi Jewish ancestry, and patients with stage I-III disease.
METHODS: Sixty studies met all inclusion criteria and were considered for this meta-analysis. These studies involved 105,220 breast cancer patients, whose 3588 (3.4%) were BRCA mutations carriers. The associations between BRCA genes mutational status and overall survival (OS), breast cancer-specific survival (BCSS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS) were evaluated using random-effect models.
RESULTS: BRCA1 mutation carriers have worse OS than BRCA-negative/sporadic cases (hazard ratio, HR 1.30, 95% CI: 1.11-1.52) and worse BCSS than sporadic/BRCA-negative cases among patients with stage I-III breast cancer (HR 1.45, 95% CI: 1.01-2.07). BRCA2 mutation carriers have worse BCSS than sporadic/BRCA-negative cases (HR 1.29, 95% CI: 1.03-1.62), although they have similar OS. Among triple negative breast cancer, BRCA1/2 mutations carriers had better OS than BRCA-negative counterpart (HR 0.49, 95% CI: 0.26-0.92). Among Ashkenazi Jewish women, BRCA1/2 mutations carriers presented higher risk of death from breast cancer (HR 1.44, 95% CI: 1.05-1.97) and of distant metastases (HR 1.82, 95% CI: 1.05-3.16) than sporadic/BRCA-negative patients.
CONCLUSION: Our results support the evaluation of BRCA mutational status in patients with high risk of harboring BRCA germline mutations to better define the prognosis of breast cancer in these patients.

Solnes LB, Javadi MS, Rowe SP
18F-FDG PET/CT Imaging of Cauda Equina Syndrome Secondary to Leptomeningeal Metastatic Breast Cancer.
Clin Nucl Med. 2016; 41(11):e485-e486 [PubMed] Related Publications
Cauda equina syndrome (CES) is an uncommon entity that may be caused by a variety of conditions. It refers to dysfunction of the ventral, dorsal, sacral, and coccygeal nerve roots in the region of the filum terminale. We present a case of a 32-year-old woman with a history of BRCA1-positive metastatic breast cancer who complained of lower extremity muscle weakness increasing over a 2-week period and decreased sensation of the lower extremities accompanied by severe constipation and suspected urinary retention with overflow incontinence. The patient underwent whole-body F-FDG PET/CT and MRI of the spine with and without gadolinium-based contrast.

Isakoff SJ, Puhalla S, Domchek SM, et al.
A randomized Phase II study of veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in BRCA1/2 metastatic breast cancer: design and rationale.
Future Oncol. 2017; 13(4):307-320 [PubMed] Related Publications
Veliparib is an orally administered poly(ADP-ribose) polymerase inhibitor that is being studied in Phase I-III clinical trials, including Phase III studies in non-small-cell lung cancer, ovarian cancer and breast cancer. Tumor cells with deleterious BRCA1 or BRCA2 mutations are deficient in homologous recombination DNA repair and are intrinsically sensitive to platinum therapy and poly(ADP-ribose) polymerase inhibitors. We describe herein the design and rationale of a Phase II trial investigating whether the addition of veliparib to temozolomide or carboplatin/paclitaxel provides clinical benefit over carboplatin/paclitaxel with placebo in patients with locally recurrent or metastatic breast cancer harboring a deleterious BRCA1 or BRCA2 germline mutation (Trial registration: EudraCT 2011-002913-12, NCT01506609).

Manfredini M, Pellacani G, Losi L, et al.
Desmoplastic melanoma: a challenge for the oncologist.
Future Oncol. 2017; 13(4):337-345 [PubMed] Related Publications
AIM: To evaluate clinical, pathologic and genetic features of desmoplastic melanoma (DM).
MATERIALS & METHODS: Analysis of all DM records from 1991 to 2015.
RESULTS: The most common location of DMs was the head and neck (69%); median age and follow-up were 60.5 and 7.3 years, respectively. A familial predisposition for DMs and others malignancies was analyzed. Thin Breslow thickness (<4.5 mm) was associated with an intraepidermal component or a previous lentigo maligna, whereas high Breslow thickness (>4.5 mm) was observed in 'pure' DM.
CONCLUSION: DM could progress from an early phase, characterized by an intraepidermal component, to late phase, characterized by a dermal nodule. This hypothesis correlates with melanoma genetic and NF1 mutation, which could be an early event in the progression of DM.

Mirza MR, Monk BJ, Herrstedt J, et al.
Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer.
N Engl J Med. 2016; 375(22):2154-2164 [PubMed] Related Publications
Background Niraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer. Methods In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was progression-free survival. Results Of 553 enrolled patients, 203 were in the gBRCA cohort (with 138 assigned to niraparib and 65 to placebo), and 350 patients were in the non-gBRCA cohort (with 234 assigned to niraparib and 116 to placebo). Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval [CI], 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P<0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications. Conclusions Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity. (Funded by Tesaro; number, NCT01847274 .).

McLachlan J, George A, Banerjee S
The current status of PARP inhibitors in ovarian cancer.
Tumori. 2016; 102(5):433-440 [PubMed] Related Publications
Recent advances in our understanding of the molecular biology of epithelial ovarian cancer have led to the development of a number of targeted therapies, including poly-ADP-ribose polymerase (PARP) inhibitors. PARP inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Early studies have shown significant efficacy for PARP inhibitors in patients with germline BRCA1/2 mutations. It has become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this therapeutic approach. Importantly, companion homologous recombination deficiency scores are being developed to help guide the selection of patients most likely to gain clinical benefit from PARP inhibition. Olaparib, the first and most extensively investigated PARP inhibitor, is now licensed in Europe for maintenance treatment of patients with platinum-sensitive relapsed BRCA-mutated (germline or somatic) high-grade serous ovarian cancer who have responded to platinum-based chemotherapy. In the United States, olaparib is licensed for treatment of patients with germline BRCA-mutated ovarian cancer who have received 3 or more lines of chemotherapy. There are a number of other PARP inhibitors in late phase clinical development in ovarian cancer including rucaparib, niraparib, veliparib, and talazoparib. This review will focus on the current evidence for PARP inhibitors in ovarian cancer and discuss ongoing clinical trials and future research directions in this rapidly evolving area.

Miller RE, Ledermann JA
The status of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in ovarian cancer, part 2: extending the scope beyond olaparib and BRCA1/2 mutations.
Clin Adv Hematol Oncol. 2016; 14(9):704-11 [PubMed] Related Publications
Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown clinical activity in epithelial ovarian cancer, leading both the US Food and Drug Administration (FDA) and the European Medicines Agency to approve olaparib for tumors characterized by BRCA1 and BRCA2 mutations. However, it is becoming increasingly evident that tumors that share molecular features with BRCA-mutant tumors-a concept known as BRCAness-also may exhibit defective homologous recombination DNA repair, and therefore will respond to PARP inhibition. A number of strategies have been proposed to identify BRCAness, including identifying defects in other genes that modulate homologous recombination and characterizing the mutational and transcriptional signatures of BRCAness. In addition to olaparib, a number of other PARP inhibitors are in clinical development. This article reviews the development of PARP inhibitors other than olaparib, and discusses the evidence for PARP inhibitors beyond BRCA1/2-mutant ovarian cancer.

Dasgupta H, Mukherjee N, Islam S, et al.
Frequent alterations of homologous recombination repair pathway in primary and chemotolerant breast carcinomas: clinical importance.
Future Oncol. 2017; 13(2):159-174 [PubMed] Related Publications
AIM: To understand the importance of homologous recombination repair pathway in development of breast carcinoma (BC), alterations of some key regulatory genes like BRCA1, BRCA2, FANCC and FANCD2 were analyzed in pretherapeutic/neoadjuvant chemotherapy (NACT)-treated BC samples.
MATERIALS & METHODS: Alterations (deletion/methylation/expression) of the genes were analyzed in 118 pretherapeutic and 41 NACT-treated BC samples.
RESULTS: High deletion/methylation (29-68%) and 64-78% overall alterations of the genes were found in the samples. Concordance was evident between alteration and protein expression of the genes. Estrogen/progesterone receptor-negative tumors showed significantly high alterations even in NACT-treated samples having low CD44 and proliferating cell nuclear antigen expression. Pretherapeutic patients with alterations showed poor prognosis.
CONCLUSION: Alterations of homologous recombination repair pathway genes are needed for the development of BC.

Apsalikov B, Manambaeva Z, Ospanov E, et al.
BRCA1 and TP53 Gene-Mutations: Family Predisposition and Radioecological Risk of Developing Breast Cancer.
Asian Pac J Cancer Prev. 2016; 17(8):4059-62 [PubMed] Related Publications
Frequencies of polymorphisms of genes BRCA1 and TP53 in breast cancer (BC) patients with a BC family history and radiation history were assessed and compared in the Semey region of Kazakhstan. The study included 60 women directly irradiated by the activities of the Semipalatinsk test site with a calculated effective equivalent dose of 500 mSv and their first generation descendants (group BC+Her+Exp); 65 women with family BC and absence of radiological history - the effective equivalent dose due to anthropogenic sources not exceeding 50 mSv (group BC+Her-Exp). The comparison group consisted of 65 women patients with breast cancer without family and radiological history (BC-Her-Exp). The control group comprised 60 women without breast cancer and without family and radiological history (nonBC). We carried out the genotyping of the polymorphisms c.2311T>C, c.4308T>C and 5382insC of the BRCA1 gene and rs1042522 of the TP53 gene. The frequency of the polymorphism c.2311T>C was significantly higher in patients of the group BC+Her+Exp than in healthy women, and of the polymorphism 5382insC in BC+Her+Exp compared to all other groups. The frequency of the rs1042522 polymorphism of TP53 was significantly higher in all groups of patients with breast cancer compared with the control group. Differences between groups of women with breast cancer were significant only in BC+Her+Exp vs. BC+Her-Exp. Combinations of polymorphisms of the genes BRCA1 and TP53 predominated in women with a family and radiological history.

Kappil M, Terry MB, Delgado-Cruzata L, et al.
Mismatch Repair Polymorphisms as Markers of Breast Cancer Prevalence in the Breast Cancer Family Registry.
Anticancer Res. 2016; 36(9):4437-41 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
BACKGROUND: Major breast cancer susceptibility genes involved in DNA repair, including BRCA1 and BRCA2, have been identified. However, mutations in these genes account for only 5-10% of identified breast cancer cases. Additional DNA repair pathway genes may also contribute to susceptibility.
MATERIALS AND METHODS: We investigated the association between 12 single nucleotide polymorphisms (SNPs) in mismatch repair (MMR) genes and breast cancer risk among 313 sister-sets enrolled in the New York site of the Breast Cancer Family Registry (BCFR) (n=744) using conditional logistic regression analysis.
RESULTS: An increase in breast cancer risk was observed for women with the MUTYH_rs3219489 variant allele (odds ratio (OR)=2.23, 95% confidence interval (CI)=1.10-4.52) and for women with the MSH2_rs2303428 variant allele (OR=1.73, 95% CI=1.00-2.99).
CONCLUSION: Deficiencies in DNA repair pathways, such as MMR, have implications for the onset of familial breast cancer.

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