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

Gene Summary

Gene:BRCA1; breast cancer 1, early onset
Summary:This gene encodes a nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:breast cancer type 1 susceptibility protein
Updated:14 December, 2014


What does this gene/protein do?
Show (74)


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 14 December 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 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (10)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerBRCA1 mutations in Breast Cancer View Publications3000
Ovarian CancerBRCA1 and Ovarian Cancer View Publications2672
-Genetic Counseling for people with BRAC1/BRCA2 mutations View Publications284
Breast Cancer, FamilialProphylactic Treatments for Women with BRCA1/BRAC2 mutations Therapy View Publications237
Prostate CancerBRCA1 and Prostate Cancer View Publications176
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 Publications133
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 Publications126
Fallopian tube cancerBRCA1 mutations in Fallopian Tube Cancer View Publications112
Cancer ScreeningBRCA1 and Cancer Screening View Publications84
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 Publications52

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

Related Links

Latest Publications: BRCA1 (cancer-related)

Ottini L
Male breast cancer: a rare disease that might uncover underlying pathways of breast cancer.
Nat Rev Cancer. 2014; 14(10):643 [PubMed] Related Publications
There are similarities between breast cancers that arise in men and women but there are also differences. What can be learned from male breast cancer to gain insight into breast cancer pathogenesis?

Related: Male Breast Cancer BRCA2 Signal Transduction

Sasaki A, Tsunoda Y, Tsuji M, et al.
Decreased miR-206 expression in BRCA1 wild-type triple-negative breast cancer cells after concomitant treatment with gemcitabine and a Poly(ADP-ribose) polymerase-1 inhibitor.
Anticancer Res. 2014; 34(9):4893-7 [PubMed] Related Publications
No targeted-therapy has been established for triple-negative breast cancer accompanied by mutations in breast cancer susceptibility gene1 (BRCA1) mutation. In the present study, using BRCA1 wild-type cells (MDA-MB-231) and BRCA1-mutated cells (MDA-MB-436), we investigated miRNA expression and apoptosis on day 1 after addition of gemcitabine-alone and in combination with poly ADP-ribose polymerase-1 (PARP1) inhibitor. After drug treatment, there were significantly fewer apoptotic BRCA1 wild-type cells than BRCA1-mutated cells. Expression of miRNA-26a, -29b, -100, and -148a increased in BRCA1 wild-type cells exposed to gemcitabine-alone and in combination with the PARP1 inhibitor. The addition of PARP1 inhibitor reduced miR-206 expression in BRCA1 wild-type cells but increased it in BRCA1-mutated cells. It was suggested that miR-206 serves as a target molecule of PARP1 inhibitor combination therapy for BRCA1 wild-type triple-negative breast cancer cells.

Related: Apoptosis Gemcitabine

King MC, Levy-Lahad E, Lahad A
Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award.
JAMA. 2014; 312(11):1091-2 [PubMed] Related Publications

Rahman N
Mainstreaming genetic testing of cancer predisposition genes.
Clin Med. 2014; 14(4):436-9 [PubMed] Related Publications

Hill SJ, Clark AP, Silver DP, Livingston DM
BRCA1 pathway function in basal-like breast cancer cells.
Mol Cell Biol. 2014; 34(20):3828-42 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Sporadic basal-like cancers (BLCs) are a common subtype of breast cancer that share multiple biological properties with BRCA1-mutated breast tumors. Despite being BRCA1(+/+), sporadic BLCs are widely viewed as phenocopies of BRCA1-mutated breast cancers, because they are hypothesized to manifest a BRCA1 functional defect or breakdown of a pathway(s) in which BRCA1 plays a major role. The role of BRCA1 in the repair of double-strand DNA breaks by homologous recombination (HR) is its best understood function and the function most often implicated in BRCA1 breast cancer suppression. Therefore, it is suspected that sporadic BLCs exhibit a defect in HR. To test this hypothesis, multiple DNA damage repair assays focused on several types of repair were performed on a group of cell lines classified as sporadic BLCs and on controls. The sporadic BLC cell lines failed to exhibit an overt HR defect. Rather, they exhibited defects in the repair of stalled replication forks, another BRCA1 function. These results provide insight into why clinical trials of poly(ADP-ribose) polymerase (PARP) inhibitors, which require an HR defect for efficacy, have been unsuccessful in sporadic BLCs, unlike cisplatin, which elicits DNA damage that requires stalled fork repair and has shown efficacy in sporadic BLCs.

Related: Breast Cancer

Santos MA, Faryabi RB, Ergen AV, et al.
DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier.
Nature. 2014; 514(7520):107-11 [PubMed] Related Publications
Self-renewal is the hallmark feature both of normal stem cells and cancer stem cells. Since the regenerative capacity of normal haematopoietic stem cells is limited by the accumulation of reactive oxygen species and DNA double-strand breaks, we speculated that DNA damage might also constrain leukaemic self-renewal and malignant haematopoiesis. Here we show that the histone methyl-transferase MLL4, a suppressor of B-cell lymphoma, is required for stem-cell activity and an aggressive form of acute myeloid leukaemia harbouring the MLL-AF9 oncogene. Deletion of MLL4 enhances myelopoiesis and myeloid differentiation of leukaemic blasts, which protects mice from death related to acute myeloid leukaemia. MLL4 exerts its function by regulating transcriptional programs associated with the antioxidant response. Addition of reactive oxygen species scavengers or ectopic expression of FOXO3 protects MLL4(-/-) MLL-AF9 cells from DNA damage and inhibits myeloid maturation. Similar to MLL4 deficiency, loss of ATM or BRCA1 sensitizes transformed cells to differentiation, suggesting that myeloid differentiation is promoted by loss of genome integrity. Indeed, we show that restriction-enzyme-induced double-strand breaks are sufficient to induce differentiation of MLL-AF9 blasts, which requires cyclin-dependent kinase inhibitor p21(Cip1) (Cdkn1a) activity. In summary, we have uncovered an unexpected tumour-promoting role of genome guardians in enforcing the oncogene-induced differentiation blockade in acute myeloid leukaemia.

Related: CDKN1A Acute Myeloid Leukemia (AML)

Vladušić T, Hrašćan R, Krušlin B, et al.
Histological groups of human postpubertal testicular germ cell tumours harbour different genetic alterations.
Anticancer Res. 2014; 34(8):4005-12 [PubMed] Related Publications
BACKGROUND: Testicular germ cell tumours are the most common malignancies in young males. Molecular biology studies of these tumours are often contradictory. Two histological groups, seminoma and non-seminoma, differ both morphologically and in malignant behaviour. Although a common cytogenetic feature is seen, namely the amplification of the 12p chromosomal region, the development mechanisms of less aggressive seminomas and more aggressive non-seminomas are unknown.
MATERIALS AND METHODS: Occurrence of structural genetic alterations was analyzed in 18 seminomas and 22 non-seminomas for genes involved in the malignant tumour phenotype: cadherin 1, Type 1, E-cadherin (Epithelial), CDH1; adenomatous polyposis coli, APC; NME/NM23 nucleoside diphosphate kinase 1, NME1; tumour protein P53, TP53; cyclin-dependent kinase inhibitor 2A, CDKN2A; retinoblastoma 1, RB1; RAD51 recombinase, RAD51; mutS homolog 2, MSH2; MutL homolog 1, MLH1; breast cancer 1, early onset, BRCA1; BCL2-Associated X Protein, BAX; ATP-Binding Cassette, Sub-Family G (WHITE), Member 2, ABCG2. Genetic alterations, loss of heterozygosity and microsatellite instability, were analyzed using restriction fragment or microsatellite repeat length polymorphisms.
RESULTS: A difference in genetic alteration occurrence between seminomas and non-seminomas was observed.
CONCLUSION: Occurrence of genetic alterations correlates with clinical behaviour of these tumours and may indicate that such alterations could occur early in the development of seminomas and non-seminomas.

Related: Germ Cell Tumors Testicular Cancer

Golan T, Kanji ZS, Epelbaum R, et al.
Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers.
Br J Cancer. 2014; 111(6):1132-8 [PubMed] Related Publications
BACKGROUND: The BRCA1/2 proteins are involved in regulation of cellular proliferation by DNA damage repair via homologous recombination. Therefore, BRCA1/2 mutation carriers with pancreatic cancer may have distinct biologic outcomes.
METHODS: Patients with BRCA1/2-associated pancreatic ductal adenocarcinoma (PDAC) diagnosed between January 1994 and December 2012 were identified from databases at three participating institutions. Clinical data were collected. Disease-free survival and overall survival (OS) were analysed.
RESULTS: Overall, 71 patients with PDAC and BRCA1 (n=21), BRCA2 (n=49) or both (n=1) mutations were identified. Mean age at diagnosis was 60.3 years (range 33-83), 81.7% (n=58) had any family history of malignancy; 30% (n=21) underwent primary resection. Out of 71 participants, 12 received experimental therapy; one patient had missing data, these 13 cases were excluded from OS analysis. Median OS for 58 patients was 14 months (95% CI 10-23 months). Median OS for patients with stage 1/2 disease has not been reached with 52% still alive at 60 months. Median OS for stage 3/4 was 12 months (95% CI 6-15). Superior OS was observed for patients with stage 3/4 treated with platinum vs those treated with non-platinum chemotherapies (22 vs 9 months; P=0.039).
CONCLUSION: Superior OS was observed for advanced-disease BRCA-associated PDAC with platinum exposure.

Related: Cisplatin Cancer of the Pancreas Pancreatic Cancer Oxaliplatin

Janavičius R, Rudaitis V, Mickys U, et al.
Comprehensive BRCA1 and BRCA2 mutational profile in Lithuania.
Cancer Genet. 2014; 207(5):195-205 [PubMed] Related Publications
There is limited knowledge about the BRCA1/2 mutational profile in Lithuania. We aimed to define the full BRCA1 and BRCA2 mutational spectrum and the clinically relevant prevalence of these gene mutations in Lithuania. A data set of 753 unrelated probands, recruited through a clinical setting, was used and consisted of 380 female breast cancer cases, 213 epithelial ovarian cancer cases, 20 breast and ovarian cancer cases, and 140 probands with positive family history of breast or ovarian cancer. A comprehensive mutation analysis of the BRCA1/2 genes by high resolution melting analysis coupled with Sanger sequencing and multiplex ligation-dependent probe amplification analysis was performed. Genetic analysis revealed 32 different pathogenic germline BRCA1/2 mutations: 20 in the BRCA1 gene and 12 in the BRCA2 gene, including four different large genomic rearrangements in the BRCA1 gene. In all, 10 novel BRCA1/2 mutations were found. Nine different recurrent BRCA1 mutations and two recurrent BRCA2 mutations were identified, which comprised 90.4% of all BRCA1/2 mutations. BRCA1 exon 1-3 deletion and BRCA2 c.658_659del are reported for the first time as recurrent mutations, pointing to a possible Baltic founder effect. Approximately 7% of breast cancer and 22% of ovarian cancer patients without family history and an estimated 0.5-0.6% of all Lithuanian women were found to be carriers of mutations in the BRCA1 or BRCA2 gene.

Related: Breast Cancer Ovarian Cancer

Kalirai H, Dodson A, Faqir S, et al.
Lack of BAP1 protein expression in uveal melanoma is associated with increased metastatic risk and has utility in routine prognostic testing.
Br J Cancer. 2014; 111(7):1373-80 [PubMed] Article available free on PMC after 23/09/2015 Related Publications
BACKGROUND: The absence of BRCA1-associated protein 1 (BAP1) expression in uveal melanoma (UM) is associated with metastatic progression and reduced survival. In this study, we examine nuclear BAP1 (nBAP1) protein expression in primary UMs (PUMs) that show both 'typical' and 'atypical' clinical courses according to their chromosome 3 status, and secondary hepatic metastatic UM (MUM), correlating the results with histological, clinical and survival data.
METHODS: Nuclear BAP1 expression was immunohistochemically assessed in tissue microarrays (TMAs) of: (a) 68 PUM patients, who had been treated surgically; and (b) 13 MUM patients, with 5 cases being paired with primary tumour tissue. All cases were fully annotated. The percentage of tumour cell nuclei staining positively for BAP1 was scored by independent observers.
RESULTS: Nuclear BAP1 protein expression was absent in 35 out of 68 (51%) PUM patients, correlating strongly with poor prognostic clinicopathological and genetic parameters and reduced survival (Log rank, P<0.001). Lack of nBAP1 expression importantly identified a subset of 'atypical' PUM patients with disomy of chromosome 3 but with unexpected metastatic relapse. Nuclear BAP1 expression was absent in 10 out of 13 (77%) MUM and expression was concordant in all paired PUM and MUM patients.
CONCLUSIONS: Absent nBAP1 protein expression is an independent survival predictor for UM patients, easily examined using immunohistochemistry.

Related: BAP1 gene

Li B, Qiu B, Lee DS, et al.
Fructose-1,6-bisphosphatase opposes renal carcinoma progression.
Nature. 2014; 513(7517):251-5 [PubMed] Article available free on PMC after 11/03/2015 Related Publications
Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is characterized by elevated glycogen levels and fat deposition. These consistent metabolic alterations are associated with normoxic stabilization of hypoxia-inducible factors (HIFs) secondary to von Hippel-Lindau (VHL) mutations that occur in over 90% of ccRCC tumours. However, kidney-specific VHL deletion in mice fails to elicit ccRCC-specific metabolic phenotypes and tumour formation, suggesting that additional mechanisms are essential. Recent large-scale sequencing analyses revealed the loss of several chromatin remodelling enzymes in a subset of ccRCC (these included polybromo-1, SET domain containing 2 and BRCA1-associated protein-1, among others), indicating that epigenetic perturbations are probably important contributors to the natural history of this disease. Here we used an integrative approach comprising pan-metabolomic profiling and metabolic gene set analysis and determined that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) is uniformly depleted in over six hundred ccRCC tumours examined. Notably, the human FBP1 locus resides on chromosome 9q22, the loss of which is associated with poor prognosis for ccRCC patients. Our data further indicate that FBP1 inhibits ccRCC progression through two distinct mechanisms. First, FBP1 antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cell of origin, thereby inhibiting a potential Warburg effect. Second, in pVHL (the protein encoded by the VHL gene)-deficient ccRCC cells, FBP1 restrains cell proliferation, glycolysis and the pentose phosphate pathway in a catalytic-activity-independent manner, by inhibiting nuclear HIF function via direct interaction with the HIF inhibitory domain. This unique dual function of the FBP1 protein explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously identified tumour suppressors that are not consistently mutated in all tumours.

Related: Kidney Cancer

Gorodnova TV, Maksimov SIa, Guseĭnov KD, Imianitov EN
[Effectiveness of platinum-based chemotherapy in ovarian cancer patients with BRCA1/2 mutations].
Vopr Onkol. 2014; 60(3):339-42 [PubMed] Related Publications
The purpose of this study was to examine the clinical significance of mutations in BRCA1/2 in the formation of response to neoadjuvant platinum-based chemotherapy for ovarian cancer (OC). All patients who had had neoadjuvant chemotherapy (NCT) in our Institute from January 2000 till January 2013 were tested for carrier of mutations in BRCA1/2. In accordance with the BRCA-status we formed two groups--a group with hereditary advanced OC and a group with non-hereditary advanced OC. In the formed groups there was studied the effectiveness of chemotherapy. Patients carriers of mutations in BRCA1/2 showed a complete clinical response in 34% of cases, compared to 4% in the non-hereditary OC. Analysis of the results of cytoreductive surgery showed that in the group of hereditary cancer it was significantly higher the percentage of performing optimal cytoreductive operations (71% vs 48%). We analyzed the cases of complete pathologic response in all patients NCT and found that full pathomorphosis significantly associated with BRCA-status and the type of ongoing chemotherapy. It was important to note that all carriers of mutations in BRCA1/2 responded to cisplatin chemotherapy.

Related: Ovarian Cancer

Cass I, Walts AE, Barbuto D, et al.
A cautious view of putative precursors of serous carcinomas in the fallopian tubes of BRCA mutation carriers.
Gynecol Oncol. 2014; 134(3):492-7 [PubMed] Related Publications
OBJECTIVE: To compare the frequency and distribution of candidate precursors of serous carcinoma in the fallopian tubes of BRCA mutation carriers to BRCA non-mutation carriers (controls) at risk-reducing bilateral salpingo-oophorectomy (RRSO).
METHODS: 78 BRCA carriers (52 BRCA1, 26 BRCA2) and 23 controls underwent RRSO. Fallopian tubes were serially cross-sectioned, and adnexa were entirely submitted and examined by two gynecologic pathologists blinded to BRCA mutation status. The presence and location of serous tubal intraepithelial carcinoma (STIC), p53 overexpression (≥ 6 consecutively stained nuclei), Ki67 overexpression, atypia/low grade dysplasia and epithelial hyperplasia were compared between BRCA carriers and controls. Patient age was dichotomized: ≤ 50 and >50 years.
RESULTS: 9 (12%) BRCA carriers had occult carcinoma: 8 STIC and 1 stage IC tubal carcinoma with STIC. No occult carcinomas or STIC was seen in controls. STIC involved the distal tube in all cases and was multifocal in three cases. STIC was more common in women >50 (p=0.06). P53 overexpression was common in BRCA carriers (30%) and controls (43%) (p=0.5) and did not correlate with age. Only 5/9 (55%) of STIC exhibited p53 overexpression. 2 patients had Ki67 overexpression: both BRCA1 carriers with STIC. No difference in the frequency of atypia/low grade dysplasia or hyperplasia was observed between BRCA carriers and controls.
CONCLUSIONS: STIC is the dominant precursor of serous fallopian tube carcinoma in BRCA carriers. There is insufficient evidence to support p53 overexpression alone as a putative precursor. Atypia/low grade dysplasia and epithelial hyperplasia are not pre-neoplastic lesions of serous fallopian tube carcinoma.

Related: Fallopian Tube Cancer BRCA2

Del Conte G, Sessa C, von Moos R, et al.
Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours.
Br J Cancer. 2014; 111(4):651-9 [PubMed] Article available free on PMC after 12/08/2015 Related Publications
BACKGROUND: Olaparib, an oral PARP inhibitor, has shown antitumour activity as monotherapy in patients with germline BRCA1/2 (gBRCA)-mutated breast and ovarian cancer. This study evaluated olaparib capsules in combination with liposomal doxorubicin (PLD) in patients with advanced solid tumours (NCT00819221).
METHODS: Patients received 28-day cycles of olaparib, continuously (days 1-28) or intermittently (days 1-7), plus PLD (40 mg m(-2), day 1); seven olaparib dose cohorts (50-400 mg bid) were explored to determine the recommended dose. Assessments included safety, pharmacokinetics, pharmacodynamics and preliminary efficacy (objective response rate (ORR)).
RESULTS: Of 44 patients treated (ovarian, n=28; breast, n=13; other/unknown, n=3), two experienced dose-limiting toxicities (grade 3 stomatitis and fatal pneumonia/pneumonitis (200 mg per 28-day cycle); grade 4 thrombocytopenia (400 mg per 7-day cycle)). The maximum tolerated dose was not reached using continuous olaparib 400 mg bid plus PLD. Grade ≥3 and serious AEs were reported for 27 (61%) and 12 (27%) patients, respectively. No major pharmacokinetic interference was observed between olaparib and PLD. The ORR was 33% (n=14 out of 42; complete response, n=3). A total of 13 responders had ovarian cancer: 10 were platinum-sensitive, 11 had a gBRCA mutation.
CONCLUSIONS: Continuous/intermittent olaparib (up to 400 mg bid) combined with PLD (40 mg m(-2)) was generally tolerated and showed evidence of antitumour activity in ovarian cancer.

Related: Breast Cancer Doxorubicin Ovarian Cancer Liposomal Doxorubicin

Kotsopoulos J, Zhang S, Akbari M, et al.
BRCA1 mRNA levels following a 4-6-week intervention with oral 3,3'-diindolylmethane.
Br J Cancer. 2014; 111(7):1269-74 [PubMed] Article available free on PMC after 23/09/2015 Related Publications
BACKGROUND: Haploinsufficiency may contribute to the development of breast cancer among women with a BRCA1 mutation. Thus, interventions that enhance BRCA1 expression may represent avenues for prevention. Studies have shown that 3,3'-diindolylmethane (DIM) can upregulate BRCA1 expression in breast cancer cells. This has yet to be demonstrated in vivo.
METHODS: We conducted a study to evaluate the ability of oral DIM to upregulate BRCA1 mRNA expression in white blood cells. A total of 18 women were enroled in the study, including 13 BRCA1 mutation carriers who received 300 mg per day of Rx Balance BioResponse DIM for 4-6 weeks (intervention group) and 5 BRCA1 mutation carriers who did not take DIM (control group). BRCA1 mRNA expression was assessed at baseline and at 4-6 weeks by real-time, quantitative PCR and the relative change in BRCA1 mRNA expression (that is, 2(-ΔΔCT)) was calculated.
RESULTS: The relative change in BRCA1 mRNA expression among women in the intervention group achieved borderline significance (P paired t-test=0.05). In the intervention group, BRCA1 mRNA expression increased in 10 of the participants, decreased in 2 and remained unchanged in 1 of the participants following DIM intervention (P sign test=0.02). On average, women in the intervention group experienced a 34% increase in BRCA1 mRNA expression (range -24 to 194%). There was no significant difference in the relative change in BRCA1 mRNA expression among women in the control group (P paired t-test=0.45).
CONCLUSIONS: Under the tested conditions, oral DIM was associated with an increase in BRCA1 mRNA expression in women with a BRCA1 mutation. The possibility of mitigating the effect of an inherited deleterious BRCA1 mutation by increasing the physiologic expression of the gene and normalising protein levels represents a clinically important paradigm shift in the prevention strategies available to these high-risk women. Future studies with a larger sample size and higher doses of DIM are warranted.

Related: Breast Cancer

Chui MH, Ryan P, Radigan J, et al.
The histomorphology of Lynch syndrome-associated ovarian carcinomas: toward a subtype-specific screening strategy.
Am J Surg Pathol. 2014; 38(9):1173-81 [PubMed] Related Publications
Women with Lynch syndrome (LS) are at increased risk for the development of epithelial ovarian cancer (OC). Analogous to previous studies on BRCA1/2 mutation carriers, there is evidence to suggest a histotype-specific association in LS-associated OCs (LS-OC). Whereas the diagnosis of high-grade serous carcinoma is an indication for BRCA1/2 germline testing, in contrast, there are no screening guidelines in place for triaging OC patients for LS testing based on histotype. We performed a centralized pathology review of tumor subtype on 20 germline mutation-confirmed LS-OCs, on the basis of morphologic assessment of hematoxylin and eosin-stained slides, with confirmation by immunohistochemistry when necessary. Results from mismatch-repair immunohistochemistry (MMR-IHC) and microsatellite instability (MSI) phenotype status were documented, and detailed pedigrees were analyzed to determine whether previously proposed clinical criteria would have selected these patients for genetic testing. Review of pathology revealed all LS-OCs to be either pure endometrioid carcinoma (14 cases), mixed carcinoma with an endometrioid component (4 cases), or clear cell carcinoma (2 cases). No high-grade or low-grade serous carcinomas or mucinous carcinomas of intestinal type were identified. Tumor-infiltrating lymphocytes were prominent (≥40 per 10 high-powered fields) in 2 cases only. With the exception of 1 case, all tumors tested for MMR-IHC or MSI had an MMR-deficient phenotype. Within this cohort, 50%, 55%, 65%, and 85% of patients would have been selected for genetic workup by Amsterdam II, revised Bethesda Guidelines, SGO 10% to 25%, and SGO 5% to 10% criteria, respectively, with <60% of index or sentinel cases detected by any of these schemas. To further support a subtype-driven screening strategy, MMR-IHC reflex testing was performed on all consecutive non-serous OCs diagnosed at 1 academic hospital over a 2-year period; MMR deficiency was identified in 10/48 (21%) cases, all with endometrioid or clear cell histology. We conclude that there is a strong association between endometrioid and clear cell ovarian carcinomas and hereditary predisposition due to MMR gene mutation. These findings have implications for the role of tumor subtype in screening patients with OC for further genetic testing and support reflex MMR-IHC and/or MSI testing for newly diagnosed cases of endometrioid or clear cell ovarian carcinoma.

Related: Canada Cancer Screening and Early Detection Ovarian Cancer

Lou DI, McBee RM, Le UQ, et al.
Rapid evolution of BRCA1 and BRCA2 in humans and other primates.
BMC Evol Biol. 2014; 14:155 [PubMed] Article available free on PMC after 23/09/2015 Related Publications
BACKGROUND: The maintenance of chromosomal integrity is an essential task of every living organism and cellular repair mechanisms exist to guard against insults to DNA. Given the importance of this process, it is expected that DNA repair proteins would be evolutionarily conserved, exhibiting very minimal sequence change over time. However, BRCA1, an essential gene involved in DNA repair, has been reported to be evolving rapidly despite the fact that many protein-altering mutations within this gene convey a significantly elevated risk for breast and ovarian cancers.
RESULTS: To obtain a deeper understanding of the evolutionary trajectory of BRCA1, we analyzed complete BRCA1 gene sequences from 23 primate species. We show that specific amino acid sites have experienced repeated selection for amino acid replacement over primate evolution. This selection has been focused specifically on humans and our closest living relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). After examining BRCA1 polymorphisms in 7 bonobo, 44 chimpanzee, and 44 rhesus macaque (Macaca mulatta) individuals, we find considerable variation within each of these species and evidence for recent selection in chimpanzee populations. Finally, we also sequenced and analyzed BRCA2 from 24 primate species and find that this gene has also evolved under positive selection.
CONCLUSIONS: While mutations leading to truncated forms of BRCA1 are clearly linked to cancer phenotypes in humans, there is also an underlying selective pressure in favor of amino acid-altering substitutions in this gene. A hypothesis where viruses are the drivers of this natural selection is discussed.

Related: Breast Cancer BRCA2 Ovarian Cancer Polymorphisms

Synowiec A, Wcisło G, Bodnar L, et al.
[Screening for ovarian cancer in BRCA1/BRCA2 mutations carriers].
Ginekol Pol. 2014; 85(5):377-81 [PubMed] Related Publications
Worldwide screening for early detection of ovarian cancer in both, the general population and the group of women at high risk for ovarian cancer including BRCA genes mutations carriers, has proven to be ineffective. The recommended screening methods, including a pelvic examination, transvaginal ultrasound, and CA125 performed biannually continue to fail due to their relatively low sensitivity specificity and positive predictive value tests, as well as the fact that cancer is still detected in advanced stages (FIGO III/IV). However proteomic techniques and the ongoing search for more sensitive and specific biomarkers to increase effectiveness of screening tests for ovarian cancer bring new hope. We reviewed the current literature on screening for ovarian cancer in BRCA genes mutations carriers.

Related: Cancer Screening and Early Detection BRCA2 Ovarian Cancer

Summaries for patients. Assessing the genetic risk for BRCA-related breast or ovarian cancer in women: recommendations from the U.S. Preventive Services Task Force.
Ann Intern Med. 2014; 160(4):I-16 [PubMed] Related Publications

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

Related: BRCA2 Polymorphisms

Park JY, Zhang F, Andreassen PR
PALB2: the hub of a network of tumor suppressors involved in DNA damage responses.
Biochim Biophys Acta. 2014; 1846(1):263-75 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
PALB2 was first identified as a partner of BRCA2 that mediates its recruitment to sites of DNA damage. PALB2 was subsequently found as a tumor suppressor gene. Inherited heterozygosity for this gene is associated with an increased risk of cancer of the breast and other sites. Additionally, biallelic mutation of PALB2 is linked to Fanconi anemia, which also has an increased risk of developing malignant disease. Recent work has identified numerous interactions of PALB2, suggesting that it functions in a network of proteins encoded by tumor suppressors. Notably, many of these tumor suppressors are related to the cellular response to DNA damage. The recruitment of PALB2 to DNA double-strand breaks at the head of this network is via a ubiquitin-dependent signaling pathway that involves the RAP80, Abraxas and BRCA1 tumor suppressors. Next, PALB2 interacts with BRCA2, which is a tumor suppressor, and with the RAD51 recombinase. These interactions promote DNA repair by homologous recombination (HR). More recently, PALB2 has been found to bind the RAD51 paralog, RAD51C, as well as the translesion polymerase pol η, both of which are tumor suppressors with functions in HR. Further, an interaction with MRG15, which is related to chromatin regulation, may facilitate DNA repair in damaged chromatin. Finally, PALB2 interacts with KEAP1, a regulator of the response to oxidative stress. The PALB2 network appears to mediate the maintenance of genome stability, may explain the association of many of the corresponding genes with similar spectra of tumors, and could present novel therapeutic opportunities.

Related: Cancer Prevention and Risk Reduction PALB2

Gevensleben H, Bossung V, Meindl A, et al.
Pathological features of breast and ovarian cancers in RAD51C germline mutation carriers.
Virchows Arch. 2014; 465(3):365-9 [PubMed] Related Publications

Printz C
Women with BRCA mutation have better survival rates after double mastectomy.
Cancer. 2014; 120(14):2071 [PubMed] Related Publications

Ledford H
Resurrected cancer drug faces regulators.
Nature. 2014; 510(7506):454 [PubMed] Related Publications

Li YT, Ni D, Yang L, et al.
The prevalence of BRCA1/2 mutations of triple-negative breast cancer patients in Xinjiang multiple ethnic region of China.
Eur J Med Res. 2014; 19:35 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
BACKGROUND: The screening of BRCA1 and BRCA2 mutations is now an established component of risk evaluation and management of familial breast cancer, early-onset breast cancer and bilateral breast cancer patients. There is still some controversy about whether this screening should be done in triple-negative breast cancers. Therefore, we evaluated the BRCA mutation prevalence in patients with triple-negative breast cancer in a multi-ethnic region of China.
METHODS: A total 96 women who were diagnosed with triple-negative breast cancer in the Xinjiang region of China were enrolled in this study. BRCA1 and BRCA2 screening was performed by polymerase chain reaction-denaturing high-performance liquid chromatography (PCR-DHPLC) sequencing analysis. All mutations were confirmed with direct sequencing.
RESULTS: The prevalence of a BRCA1/2 germline mutation was about 25% (24/96) in the Xinjiang region of China. Among 35 selected cases with a family history and/or bilateral breast cancers, the BRCA1/2 mutation prevalence was 25.7% (9/35). Of the remaining 61 patients with unselected triple-negative breast cancer, the BRCA1/2 mutation prevalence was 24.6% (15/61), and all 15 individuals with these mutations were premenopausal patients.
CONCLUSIONS: These results suggest that premenopausal women with triple-negative breast cancer may be candidates for genetic testing for BRCA1/2 in the Xinjiang region of China, even in the absence of a family history or bilateral breast cancer.

Related: BRCA2

Chiarelli AM, Prummel MV, Muradali D, et al.
Effectiveness of screening with annual magnetic resonance imaging and mammography: results of the initial screen from the ontario high risk breast screening program.
J Clin Oncol. 2014; 32(21):2224-30 [PubMed] Related Publications
PURPOSE: The Ontario Breast Screening Program expanded in July 2011 to screen women age 30 to 69 years at high risk for breast cancer with annual magnetic resonance imaging (MRI) and digital mammography. To the best of our knowledge, this is the first organized screening program for women at high risk for breast cancer.
PATIENTS AND METHODS: Performance measures after assessment were compared with screening results for 2,207 women with initial screening examinations. The following criteria were used to determine eligibility: known mutation in BRCA1, BRCA2, or other gene predisposing to a markedly increased risk of breast cancer, untested first-degree relative of a gene mutation carrier, family history consistent with hereditary breast cancer syndrome and estimated personal lifetime breast cancer risk ≥ 25%, or radiation therapy to the chest (before age 30 years and at least 8 years previously).
RESULTS: The recall rate was significantly higher among women who had abnormal MRI alone (15.1%; 95% CI, 13.8% to 16.4%) compared with mammogram alone (6.4%; 95% CI, 5.5% to 7.3%). Of the 35 breast cancers detected (16.3 per 1,000; 95% CI, 11.2 to 22.2), none were detected by mammogram alone, 23 (65.7%) were detected by MRI alone (10.7 per 1,000; 95% CI, 6.7 to 15.8), and 25 (71%) were detected among women who were known gene mutation carriers (30.8 per 1,000, 95% CI, 19.4 to 43.7). The positive predictive value was highest for detection based on mammogram and MRI (12.4%; 95% CI, 7.3% to 19.3%).
CONCLUSION: Screening with annual MRI combined with mammography has the potential to be effectively implemented into an organized breast screening program for women at high risk for breast cancer. This could be considered an important management option for known BRCA gene mutation carriers.

Related: Breast Cancer Cancer Screening and Early Detection

Hayden EC
Cancer-gene data sharing boosted.
Nature. 2014; 510(7504):198 [PubMed] Related Publications

Kriege M, Hollestelle A, Jager A, et al.
Survival and contralateral breast cancer in CHEK2 1100delC breast cancer patients: impact of adjuvant chemotherapy.
Br J Cancer. 2014; 111(5):1004-13 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
BACKGROUND: We assessed the sensitivity to adjuvant chemotherapy in cell cycle checkpoint kinase 2 (CHEK2) vs non-CHEK2 breast cancer patients by comparing the contralateral breast cancer incidence and distant disease-free and breast cancer-specific survival between both groups, stratified for adjuvant chemotherapy.
METHODS: One Dutch hereditary non-BRCA1/2 breast cancer patient cohort (n=1220) and two Dutch cohorts unselected for family history (n=1014 and n=2488, respectively) were genotyped for CHEK2 1100delC. Hazard ratios for contralateral breast cancer, distant disease-free and breast cancer-specific death for mutation carriers vs noncarriers were calculated using the Cox proportional hazard method, stratified for adjuvant chemotherapy.
RESULTS: The CHEK2 mutation carriers (n=193) had an increased incidence of contralateral breast cancer (multivariate hazard ratio 3.97, 95% confidence interval 2.59-6.07). Distant disease-free and breast cancer-specific survival were similar in the first 6 years in mutation carriers compared with noncarriers, but diverted as of 6 years after breast cancer diagnosis (multivariate hazard ratios and 95% confidence intervals 2.65 (1.79-3.93) and 2.05 (1.41-2.99), respectively). No significant interaction between CHEK2 and adjuvant chemotherapy was observed.
CONCLUSIONS: The CHEK2 1100delC-associated breast cancer is associated with a higher contralateral breast cancer rate as well as worse survival measures beyond 6 years after diagnosis. No differential sensitivity to adjuvant chemotherapy was observed in CHEK2 patients.

Related: Breast Cancer CHEK2

Lokich E, Stuckey A, Raker C, et al.
Preoperative genetic testing affects surgical decision making in breast cancer patients.
Gynecol Oncol. 2014; 134(2):326-30 [PubMed] Related Publications
OBJECTIVES: Our aim was to determine if BRCA mutation status changes surgical decision making in women who undergo genetic testing after the diagnosis of breast cancer.
METHODS: This is a retrospective cohort study of breast cancer patients who had BRCA mutation testing performed prior to surgery. We compared surgical choice and change in surgical choice in women who tested positive for a BRCA mutation with those who tested negative. Surgery was considered the most definitive surgery within a year of diagnosis. Other data collected included age, race, stage, histology, receptor status, adjuvant treatment, gravity, parity, and family history. Variables were compared by BRCA status using Fisher's exact test and logistic regression.
RESULTS: Three hundred and two women were included. Thirty-two (10.6%) were identified as carrying a BRCA mutation. Most women had early stage disease (55.6% T1 lesions, 72.8% node negative); 55.6% had breast-conserving surgery, and the remaining had unilateral or bilateral mastectomy. BRCA mutation carriers were more likely to have both a personal history of breast cancer (RR 2.74, 95% CI=1.08-6.98) and hormone receptor-negative tumors (56.0% vs. 26.2%, p=0.002). BRCA mutation carriers were more likely to choose bilateral mastectomy with reconstruction (56.3% vs. 15.9%, p<0.0001); 71.9% of BRCA mutation carriers opted for a different surgery than what was initially planned by their surgeon as compared to 29% of mutation-negative patients (p<0.0001).
CONCLUSIONS: BRCA mutation testing strongly influences surgical decision making in newly diagnosed breast cancer patients. For women who meet NCCN referral guidelines, genetic evaluation should be performed prior to surgical intervention.

Related: Breast Cancer BRCA2

Ruscito I, Dimitrova D, Vasconcelos I, et al.
BRCA1 gene promoter methylation status in high-grade serous ovarian cancer patients--a study of the tumour Bank ovarian cancer (TOC) and ovarian cancer diagnosis consortium (OVCAD).
Eur J Cancer. 2014; 50(12):2090-8 [PubMed] Related Publications
BACKGROUND: Mutations in BRCA1/2 genes are involved in the pathogenesis of breast and ovarian cancer. Inactivation of these genes can also be mediated by hypermethylation of CpGs in the promoter regions. Aim of this study was to analyse the clinical impact of BRCA1 promoter gene methylation status in a homogenous cohort of high-grade serous ovarian cancer (HGSOC) patients.
METHODS: The cohort included 257 primary HGSOC patients treated by cytoreduction and platinum-based chemotherapy. DNA was extracted from fresh frozen tissue samples. BRCA1 gene promoter methylation rate was assessed using polymerase chain reaction (PCR).
RESULTS: 14.8% of patients presented hypermethylation within a selected region of the BRCA1 promoter. The rate of hypermethylation was significantly higher in younger patients (20.8% hypermethylation in the age group ⩽ 58 years versus 8.7% hypermethylation in the age group >58 years; p = 0.008). Optimal tumour debulking could be reached in 63% of patients, without significant differences in the extent of residual disease with respect to the methylation status. No impact of BRCA1 gene promoter methylation status on progression free- and overall-survival rates was found. No significant differences within BRCA1 promoter methylation status between primary and metastatic tissue could be observed. These results on BRCA1 promoter methylation status were also confirmed in a subgroup of 107 patients found negative for BRCA1 exon 11 mutations.
CONCLUSIONS: Our data suggest that BRCA1 methylation determines the earlier onset of HGSOC. Furthermore our study supports the idea that BRCAness is not only due to mutations but also to epigenetic changes in BRCA1 promoter gene.

Related: Ovarian Cancer


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Cite this page: Cotterill SJ. BRCA1, Cancer Genetics Web: http://www.cancerindex.org/geneweb/BRCA1.htm Accessed: date

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