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
Source:NCBIAccessed: 15 February, 2015


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 (1990-2015)
Graph generated 15 February 2015 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 15 February, 2015 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
Breast CancerBRCA1 mutations in Breast Cancer View Publications3000
Ovarian CancerBRCA1 and Ovarian Cancer View Publications2709
-Genetic Counseling for people with BRAC1/BRCA2 mutations View Publications290
Breast Cancer, FamilialProphylactic Treatments for Women with BRCA1/BRAC2 mutations Therapy View Publications237
Prostate CancerBRCA1 and Prostate Cancer View Publications177
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 Publications127
Fallopian tube cancerBRCA1 mutations in Fallopian Tube Cancer View Publications116
Cancer ScreeningBRCA1 and Cancer Screening View Publications90
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 Publications57

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)

King MC, Lahad A, Levy-Lahad E
Proposed shift in screening for breast cancer--reply.
JAMA. 2015; 313(5):525-6 [PubMed] Related Publications

Levine B, Steinberg K
Proposed shift in screening for breast cancer.
JAMA. 2015; 313(5):525 [PubMed] Related Publications

Popovska S, Ivanov I, Dineva T, et al.
[Morphologically qnd immunohistochemically based screening criteria for selection of patients with possible mutation of BRCA1 gene in primary ovarian cancer].
Akush Ginekol (Sofiia). 2014; 53(4):21-8 [PubMed] Related Publications
UNLABELLED: SUMMARY AND AIM: Breast cancer (BC) and Ovarian cancer (OC) are some of the most common cancers affecting women. Environmental factors and genetic alterations are involved in the etiology of both cancers. The main susceptibility genes that predisposed to BC and OC are BRCA1 (BReast CAncer 1) and BRCA 2 (BReast CAncer 2). Those of BC and OC which are due to germline mutation in BRCA 1/2 are defined as hereditary. Because of the expensiveness of genetic testing for mutations in BRCA1 we aimed to select patients with ovarian cancer suitable for genetic testing, on the base of certain morphological and immunohistochemical criteria.
MATERIAL AND METHODS: We have conducted a retrospective analysis of 29 cases with serous papillary OC, taken from the archives of the Department of Clinical Pathology, University Hospital "Dr. G. Stranski" Pleven. We performed morphological assessment and subsequent immunohistochemical study with antibodies against p53, anti BRCA1 and anti proliferative marker Ki-67.
RESULTS: Nineteen (65.52%) of all 29 cases were found with loss of immunohistochemical expression of BRCA1 and we defined them as suitable for genetic testing of BRCA1 mutations.
CONCLUSION: A set of morphological and immunohistochemical criteria allows screening of women that should be referred for genetic testing, as it is expensive, and the incidence of BRCA1 mutations in the general population is very low.

Couzin-Frankel J
Unknown significance.
Science. 2014; 346(6214):1167-70 [PubMed] Related Publications

Olariu R, Shafighi M, Constantinescu MA
[The risk-reducing mastectomy: unnecessary hysteria or life-saving prophylaxis?].
Ther Umsch. 2014; 71(12):759-64 [PubMed] Related Publications
The prophylactic (risk-reducing) mastectomy is a world-wide recognized method for specifically treating the increased breast cancer risk in patients showing a BRCA1 and/or BRCA2 mutation as well as other patient groups at increased breast cancer risk. This option should be offered to all patients having the pertinent risk profile. Breast reconstruction is an integral part of the risk-reducing mastectomy procedure and all possible methods of breast reconstruction, especially autologous tissue reconstruction should be offered to all patients having a medical indication and desiring this surgical treatment. These patients are best managed in certified Breast Care Centres where the different medical and surgical specialists can address interdisciplinary all aspects of genetic counselling, preoperative counselling, mastectomy and reconstructive techniques as well as the necessary postoperative surveillance.

Arai M, Iwase T, Takazawa Y, Takeshima N
[Current clinical issues and recent trends in hereditary breast and ovarian cancer in Japan-genetic testing for HBOC and risk-reducing surgery].
Gan To Kagaku Ryoho. 2014; 41(11):1333-9 [PubMed] Related Publications
The recognition of hereditary breast and ovarian cancer (HBOC) is gradually spreading in Japan after a famous American actress made it public that she underwent risk-reducing mastectomy (RRM) based on mutation of BRCA1. HBOC is a cancer susceptibility syndrome involving breast, ovarian, or prostate cancers due to germline mutation of BRCA1 or BRCA2. Although the frequency is low, genomic rearrangement is also found in Japan; therefore, in addition to PCR-direct sequencing, multiplex ligation-dependent probe amplification (MLPA) should be performed in genetic testing for HBOC. Recently, candidate genes other than BRCA1/2, such as RAD51C, PALB2, and BRIP1, have been identified for hereditary breast cancers. Variants of uncertain significance are seen in approximately 4-6% of all genetic testing reports for BRCA1/2. ACMG recommends the use of the term"variant"in addition to a modifier such as pathogenic, benign, and so on, instead of terms such as mutation or polymorphism. The incidence of ovarian cancer is not increased in women from breast cancer-only families that test negative for BRCA1/2 mutations. Therefore, intensive gynecological surveillance may not be needed for these clients. Basic data such as penetrance and cumulative risks of HBOC in Japanese populations are insufficient for risk assessment in genetic counseling. The Japanese HBOC consortium was established, and as one of the activities of the consortium, the registration project will start to provide essential genetic information in clinical practice. In Japan risk-reducing surgeries are, albeit gradually, increasingly being performed to potentially protect mutation carriers against HBOC. Risk-reducing salpingo-oophorectomy (RRSO) is effective in the reduction of the incidence of breast cancer, as well as of ovarian cancer. Furthermore, RRSO is associated with improved overall survival in BRCA1/2 mutation carriers. RRM also reduces the risk of breast cancer by more than 90%, but the survival benefit remains unknown. Recently, contralateral RRM has shown improved overall survival in a prospective analysis. Pathological examination of resected surgical specimens from RRSO revealed that some serous ovarian carcinomas originated from fimbriae of the uterine tube, showing focal p53 overexpression (p53 signature) in the tubal epithelium. Therefore, initial bilateral salpingectomy followed by a delayed oophorectomy may be a proposed alternative to RRSO, but there is no prospective evidence on the efficacy of bilateral salpingectomy.

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?

Kinney AY, Butler KM, Schwartz MD, et al.
Expanding access to BRCA1/2 genetic counseling with telephone delivery: a cluster randomized trial.
J Natl Cancer Inst. 2014; 106(12) [PubMed] Related Publications
BACKGROUND: The growing demand for cancer genetic services underscores the need to consider approaches that enhance access and efficiency of genetic counseling. Telephone delivery of cancer genetic services may improve access to these services for individuals experiencing geographic (rural areas) and structural (travel time, transportation, childcare) barriers to access.
METHODS: This cluster-randomized clinical trial used population-based sampling of women at risk for BRCA1/2 mutations to compare telephone and in-person counseling for: 1) equivalency of testing uptake and 2) noninferiority of changes in psychosocial measures. Women 25 to 74 years of age with personal or family histories of breast or ovarian cancer and who were able to travel to one of 14 outreach clinics were invited to participate. Randomization was by family. Assessments were conducted at baseline one week after pretest and post-test counseling and at six months. Of the 988 women randomly assigned, 901 completed a follow-up assessment. Cluster bootstrap methods were used to estimate the 95% confidence interval (CI) for the difference between test uptake proportions, using a 10% equivalency margin. Differences in psychosocial outcomes for determining noninferiority were estimated using linear models together with one-sided 97.5% bootstrap CIs.
RESULTS: Uptake of BRCA1/2 testing was lower following telephone (21.8%) than in-person counseling (31.8%, difference = 10.2%, 95% CI = 3.9% to 16.3%; after imputation of missing data: difference = 9.2%, 95% CI = -0.1% to 24.6%). Telephone counseling fulfilled the criteria for noninferiority to in-person counseling for all measures.
CONCLUSIONS: BRCA1/2 telephone counseling, although leading to lower testing uptake, appears to be safe and as effective as in-person counseling with regard to minimizing adverse psychological reactions, promoting informed decision making, and delivering patient-centered communication for both rural and urban women.

Connell TF
Patient-activated controlled expansion for breast reconstruction using controlled carbon dioxide inflation: confirmation of a feasibility study.
Plast Reconstr Surg. 2014; 134(4):503e-11e [PubMed] Related Publications
BACKGROUND: Women with breast cancer or those at high risk of developing breast cancer because of familial history of the disease or genetic mutations are frequently indicated for therapeutic or prophylactic mastectomy. Prosthetic reconstruction of the breast with placement of tissue expanders followed by implants offers favorable aesthetic and psychological results while adding only minimal additional surgical intervention. This study describes the confirmatory phase of an earlier feasibility trial that involved seven women who successfully underwent patient-activated controlled expansion for breast reconstruction with 10 AeroForm patient-controlled tissue expanders.
METHODS: A prospective, open-label, single-arm, single-surgeon confirmatory study in Perth, Australia, evaluated outcomes of two-stage breast reconstruction using the investigational device. Each subject administered a preset 10-cc dose of carbon dioxide gas using a remote dosage controller, three times each day, with a 3-hour lockout between doses until full expansion was achieved.
RESULTS: Thirty-three women with breast cancer, family history, or predisposition because of the BRCA1 or BRCA2 gene mutation underwent pedicled latissimus dorsi flap procedures with placement of 61 carbon dioxide-based tissue expanders. The mean number of days for subjects to achieve desired expansion was 17 ± 5. Operating the dosage controller was described by the surgeon as very easy in 94 percent of the cases and by 97 percent of the subjects. No serious adverse events were reported.
CONCLUSION: This study confirms that the AeroForm breast tissue expander has demonstrated the ability to provide, relative to saline expanders, a needle-free, patient-controlled, convenient, and time-saving method of tissue expansion.

Freund R, Kelsberg G, Safranek S
Clinical Inquiry: do oral contraceptives put women with a family history of breast cancer at increased risk?
J Fam Pract. 2014; 63(9):540, 549 [PubMed] Related Publications
A systematic review of the effect of combined OCPs on women with a family history of breast cancer found no additional increase in risk. Investigators identified 3 retrospective cohort studies (N=66,500, with 8500 cases) and 7 case-control studies (total 10,500 cases) from the past 40 years, most including women from the United States and Canada, but one including women from 5 continents.

Kelly PA, Connors LM
BRCA genetic testing: State of the science.
Nurse Pract. 2014; 39(11):9 [PubMed] Related Publications

Chikarmane SA, Tirumani SH, Howard SA, et al.
Metastatic patterns of breast cancer subtypes: what radiologists should know in the era of personalized cancer medicine.
Clin Radiol. 2015; 70(1):1-10 [PubMed] Related Publications
There is accumulating evidence that molecular phenotyping of breast cancer determines the timing, pattern, and outcome of metastatic disease. The most clinically relevant subtypes are hormonal-positive [oestrogen and progesterone receptor (ER/PR) positive], HER2 expressing, and triple-negative breast cancers (TNBCs). ER/PR-positive breast cancers demonstrate the best prognosis; however, metastases, in particular osseous disease, may develop much later. HER2-expressing breast cancers, although aggressive, have improved outcomes due to the advent of HER2-targeted therapies, with increased risk of central nervous system (CNS) relapses later. Finally, TNBCs present in younger women, BRCA1 mutations carriers, and carry the worst overall prognosis, with high incidence of CNS metastases, especially during the first 5 years of diagnosis. It is important for radiologists to understand the nuances of these breast cancer subtypes to predict metastatic behaviours and guide possible imaging surveillance.

King MC
Lasker Award winner Mary-Claire King.
Nat Med. 2014; 20(10):1124-5 [PubMed] Related Publications

van der Wijst MG, Brown R, Rots MG
Nrf2, the master redox switch: the Achilles' heel of ovarian cancer?
Biochim Biophys Acta. 2014; 1846(2):494-509 [PubMed] Related Publications
Ovarian cancer is the most lethal gynecological tumor type in the world due to late stage detection, and resistance to chemotherapy. Therefore, alternative additional therapies are required. The etiology of ovarian cancer remains largely unknown, but risk factors point toward an important role for oxidative stress. Both healthy and tumor cells can cope with oxidative stress by activating the transcription factor Nrf2 (also known as Nfe2l2), the master regulator of antioxidant and cytoprotective genes. Indeed, for most ovarian cancers, aberrant activation of Nrf2 is observed, which is often associated with a copy number loss within the Nrf2-inhibitory complex KEAP1-CUL3-RBX1. A key role for Nrf2 in ovarian carcinogenesis has been validated by siRNA studies. However, to exploit the Nrf2 pathway for therapeutic interventions, potential side-effects should be minimized. In this review, we explore ovarian cancer specific factors with links to aberrant activity of Nrf2, to be exploited in future combination strategies, synergistic with direct Nrf2 inhibitory drugs. Particularly, we propose to stratify patients based on common ovarian cancer mutations (KRAS, BRAF, ERBB2, BRCA1 and its link with estradiol, TP53) for future NRF2 targeting strategies.

Bai F, Chan HL, Scott A, et al.
BRCA1 suppresses epithelial-to-mesenchymal transition and stem cell dedifferentiation during mammary and tumor development.
Cancer Res. 2014; 74(21):6161-72 [PubMed] Related Publications
BRCA1 mutation carriers are predisposed to developing basal-like breast cancers with high metastasis and poor prognosis. Yet, how BRCA1 suppresses formation of basal-like breast cancers is still obscure. Deletion of p18(Ink4c) (p18), an inhibitor of CDK4 and CDK6, functionally inactivates the RB pathway, stimulates mammary luminal stem cell (LSC) proliferation, and leads to spontaneous luminal tumor development. Alternately, germline mutation of Brca1 shifts the fate of luminal cells to cause luminal-to-basal mammary tumor transformation. Here, we report that disrupting Brca1 by either germline or epithelium-specific mutation in p18-deficient mice activates epithelial-to-mesenchymal transition (EMT) and induces dedifferentiation of LSCs, which associate closely with expansion of basal and cancer stem cells and formation of basal-like tumors. Mechanistically, BRCA1 bound to the TWIST promoter, suppressing its activity and inhibiting EMT in mammary tumor cells. In human luminal cancer cells, BRCA1 silencing was sufficient to activate TWIST and EMT and increase tumor formation. In parallel, TWIST expression and EMT features correlated inversely with BRCA1 expression in human breast cancers. Together, our findings showed that BRCA1 suppressed TWIST and EMT, inhibited LSC dedifferentiation, and repressed expansion of basal stem cells and basal-like tumors. Thus, our work offers the first genetic evidence that Brca1 directly suppresses EMT and LSC dedifferentiation during breast tumorigenesis.

Kessenich CR, Flanagan M
MRI screening for breast cancer in high-risk patients.
Nurse Pract. 2014; 39(10):10-1 [PubMed] Related Publications

Burki TK
Epigenetic test for breast cancer.
Lancet Oncol. 2014; 15(9):e366 [PubMed] Related Publications

Liu JF, Barry WT, Birrer M, et al.
Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study.
Lancet Oncol. 2014; 15(11):1207-14 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
BACKGROUND: Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer.
METHODS: In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with, number NCT01116648.
FINDINGS: Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib. Median PFS was 17·7 months (95% CI 14·7-not reached) for the women treated with cediranib plus olaparib compared with 9·0 months (95% CI 5·7-16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23-0·76; p=0·005). Grade 3 and 4 adverse events were more common with combination therapy than with monotherapy, including fatigue (12 patients in the cediranib plus olaparib group vs five patients in the olaparib monotherapy group), diarrhoea (ten vs none), and hypertension (18 vs none).
INTERPRETATION: Cediranib plus olaparib seems to improve PFS in women with recurrent platinum-sensitive high-grade serous or endometrioid ovarian cancer, and warrants study in a phase 3 trial. The side-effect profile suggests such investigations should include assessments of quality of life and patient-reported outcomes to understand the effects of a continuing oral regimen with that of intermittent chemotherapy.
FUNDING: American Recovery and Reinvestment Act grant from the National Institutes of Health (NIH) (3 U01 CA062490-16S2); Intramural Program of the Center for Cancer Research; and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH.

Alli E, Solow-Cordero D, Casey SC, Ford JM
Therapeutic targeting of BRCA1-mutated breast cancers with agents that activate DNA repair.
Cancer Res. 2014; 74(21):6205-15 [PubMed] Related Publications
Cancers due to germline mutations in the BRCA1 gene tend to lack targets for approved chemoprevention agents. This study aimed at a targeted chemoprevention strategy for BRCA1-associated malignancies. Mutant BRCA1 limits the base-excision DNA repair activity that addresses oxidative DNA damage, the accumulation of which heightens one's risk for cancer. Therefore, we conducted a high-throughput chemical screen to identify drug candidates that could attenuate the inhibitory effects of mutant BRCA1 on this repair activity, thereby describing a new class of DNA repair-activating chemopreventive agents. In the screen design, such drugs functioned by enhancing base-excision DNA repair of oxidative DNA damage in the presence of mutant BRCA1, with minimal cytotoxicity. We identified at least one new agent that decreased malignant properties associated with tumorigenesis, including anchorage-independent growth and tumor progression. This work offers a preclinical proof-of-concept for a wholly new approach to chemoprevention in carriers of BRCA1 mutations as a strategy to reduce the prevalence of BRCA1-associated malignancy.

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.

Sherman ME, Piedmonte M, Mai PL, et al.
Pathologic findings at risk-reducing salpingo-oophorectomy: primary results from Gynecologic Oncology Group Trial GOG-0199.
J Clin Oncol. 2014; 32(29):3275-83 [PubMed] Article available free on PMC after 10/10/2015 Related Publications
PURPOSE: Risk-reducing salpingo-oophorectomy (RRSO) lowers mortality from ovarian/tubal and breast cancers among BRCA1/2 mutation carriers. Uncertainties persist regarding potential benefits of RRSO among high-risk noncarriers, optimal surgical age, and anatomic origin of clinically occult cancers detected at surgery. To address these topics, we analyzed surgical treatment arm results from Gynecologic Oncology Group Protocol-0199 (GOG-0199), the National Ovarian Cancer Prevention and Early Detection Study.
PARTICIPANTS AND METHODS: This analysis included asymptomatic high-risk women age ≥ 30 years who elected RRSO at enrollment. Women provided risk factor data and underwent preoperative cancer antigen 125 (CA-125) serum testing and transvaginal ultrasound (TVU). RRSO specimens were processed according to a standardized tissue processing protocol and underwent central pathology panel review. Research-based BRCA1/2 mutation testing was performed when a participant's mutation status was unknown at enrollment. Relationships between participant characteristics and diagnostic findings were assessed using univariable statistics and multivariable logistic regression.
RESULTS: Invasive or intraepithelial ovarian/tubal/peritoneal neoplasms were detected in 25 (2.6%) of 966 RRSOs (BRCA1 mutation carriers, 4.6%; BRCA2 carriers, 3.5%; and noncarriers, 0.5%; P < .001). In multivariable models, positive BRCA1/2 mutation status (P = .0056), postmenopausal status (P = .0023), and abnormal CA-125 levels and/or TVU examinations (P < .001) were associated with detection of clinically occult neoplasms at RRSO. For 387 women with negative BRCA1/2 mutation testing and normal CA-125 levels, findings at RRSO were benign.
CONCLUSION: Clinically occult cancer was detected among 2.6% of high-risk women undergoing RRSO. BRCA1/2 mutation, postmenopausal status, and abnormal preoperative CA-125 and/or TVU were associated with cancer detection at RRSO. These data can inform management decisions among women at high risk of ovarian/tubal cancer.

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

Hurst JH
Pioneering geneticist Mary-Claire King receives the 2014 Lasker~Koshland Special Achievement Award in Medical Science.
J Clin Invest. 2014; 124(10):4148-51 [PubMed] Article available free on PMC after 01/10/2015 Related Publications

Rybchenko LA, Bychkova AM, Skyban GV, Klymenko SV
Prognosis of probability of BRCA1 and BRCA2 mutations carriage in women with compromised family history of breast and/or ovarian cancer.
Probl Radiac Med Radiobiol. 2013; (18):253-60 [PubMed] Related Publications
UNLABELLED: Burdened family history of breast and/or ovarian cancer may indicate the mutations carriage in the BRCA1 and BRCA2 genes.
OBJECTIVE: Estimation and compare of the Manchester Scoring system, Penn II and Myriad algorithm in an ability to distinguish the cases with BRCA1/2 mutation those and no mutant alleles at the individual level among the Ukrainian women with early onset of a breast cancer and/or compromised family history with breast cancer and/or ovarian cancer.
MATERIAL AND METHODS: Results of genealogy, molecular genetic and morphological study from 44 females with breast cancer, with early development of the disease or family history of a breast cancer and/or ovarian cancer were the material of research. Determination of carriers BRCA1 and BRCA2 mutations among women was performed by Manchester Scoring system and Penn II and Myriad algorithm.
RESULTS AND CONCLUSIONS: Manchester Scoring system has better capacity to distinguish patients with and without mutant alleles at the individual level. The area under the curve of Manchester Scoring system is 0.84, Penn II - 0.66, Myriad - 0.68.

Otani Y, Miyake T, Kagara N, et al.
BRCA1 promoter methylation of normal breast epithelial cells as a possible precursor for BRCA1-methylated breast cancer.
Cancer Sci. 2014; 105(10):1369-76 [PubMed] Related Publications
The breast cancer susceptibility gene 1 (BRCA1) and glutathione S-transferase P1 (GSTP1) promoters are reportedly often methylated in breast cancer tissues. Their methylation status in surrounding normal breast tissues has not been examined thoroughly although this may well be important for a better understanding of breast carcinogenesis. In this study, BRCA1 and GSTP1 promoter methylation was examined by methylation-specific PCR assay. Patients with BRCA1-methylated (n = 15) or BRCA1-unmethylated (n = 15) tumors and those with GSTP1-methylated (n = 9) or GSTP1-unmethylated (n = 11) tumors were included in the present study. Methylation status of manually micro-dissected normal epithelial cells from the formalin-fixed paraffin-embedded sections of normal breast tissues adjacent to and distant from the tumors was examined at multiple sites (n = 1-5). Of the 15 patients with BRCA1-methylated tumors, 9 harbored BRCA1 promoter methylation in at least one site of the normal breast tissues. However, no BRCA1 promoter methylation was observed at any site of the normal tissues of the 15 patients with BRCA1-unmethylated tumors. No GSTP1 promoter methylation was observed in the normal tissues regardless of the methylation status of the tumors. The presence of BRCA1 promoter methylation in the normal tissues was confirmed in the epithelial cells enriched with the magnetic-activated cell sorting method. Our findings suggest that a small proportion of normal breast epithelial cells with BRCA1 promoter methylation can be precursor cells from which BRCA1-methylated breast tumors may originate. This does not apply to GSTP1 promoter methylation.

Rahman N
Mainstreaming genetic testing of cancer predisposition genes.
Clin Med. 2014; 14(4):436-9 [PubMed] Article available free on PMC after 01/10/2015 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.

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.

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.

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.

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