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:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:breast cancer type 1 susceptibility protein
Source:NCBIAccessed: 30 August, 2019


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 (1994-2019)
Graph generated 30 August 2019 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 30 August, 2019 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 Publications403
Breast Cancer, FamilialProphylactic Treatments for Women with BRCA1/BRAC2 mutations Therapy View Publications282
Prostate CancerBRCA1 and Prostate Cancer View Publications261
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 Publications191
Cancer ScreeningBRCA1 and Cancer Screening View Publications218
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 Publications147
Fallopian tube cancerBRCA1 mutations in Fallopian Tube Cancer View Publications163
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 Publications178

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)

Domchek S, Robson M
Broadening Criteria for BRCA1/2 Evaluation: Placing the USPSTF Recommendation in Context.
JAMA. 2019; 322(7):619-621 [PubMed] Related Publications

Guney Eskiler G
Talazoparib to treat BRCA-positive breast cancer.
Drugs Today (Barc). 2019; 55(7):459-467 [PubMed] Related Publications
Talazoparib tosylate (BMN-673, Talzenna; Pfizer) is an oral poly [ADP-ribose] polymerase (PARP) inhibitor (PARPi) that has been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of germline BRCA-mutated locally advanced or metastatic breast cancer (BC). In preclinical and clinical studies, talazoparib exerted superior efficacy and offered a significant clinical benefit in advanced or metastatic BC patients harboring germline BRCA mutations compared with other PARPi and standard chemotherapy regimens through the concept of synthetic lethality. Thus, this review provides insight into the results of preclinical and clinical studies, highlights the current challenges of talazoparib and suggests innovative approaches to further improve its clinical efficacy and expand the use of talazoparib in advanced BC and/or triple-negative BC treatments beyond BRCA mutations.

Inuzuka M, Nakamura S
[Hereditary Breast and Ovarian Cancer Syndrome].
Gan To Kagaku Ryoho. 2019; 46(7):1109-1113 [PubMed] Related Publications
Recently, olaparib(brand name: Lynparza Tablets)-a PARP inhibitor-has been approved for national health insurance coverage in Japan as a drug for unresectable or recurrent, BRCA1/2-positive, HER2-negative breast cancer in patients with a history of cancer chemotherapy. The addition of BRCA1/2 genetic testing as a companion diagnostic tool to the health insurance coverage is of considerable significance as a spearhead of health insurance medical care for all different types of hereditary tumors. However, several problems related to this companion diagnostic test have emerged, including the estab- lishment of a genetic counseling system and handling of BRCA1/2 genetic tests performed at the patients' own expense. In addition, the purpose of the companion diagnostic test is to confirm drug indication in a case. However, since the test results include the diagnosis of hereditary tumors, there is also an urgent need to improve the medical care system and social environment for family members of patients with pathological mutations. The use of genetic analysis is widespread in the clinical settings, and genetic medical care is anticipated to advance in the future. Therefore, it would be pivotal to come up with measures against hereditary tumors, such as hereditary breast and ovarian cancer(HBOC)syndrome. In this chapter, we describe the current status and prospects of HBOC medical care, with a particular focus on companion diagnostics.

Golan T, Hammel P, Reni M, et al.
Maintenance Olaparib for Germline
N Engl J Med. 2019; 381(4):317-327 [PubMed] Related Publications
BACKGROUND: Patients with a germline
METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline
RESULTS: Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event.
CONCLUSIONS: Among patients with a germline

Budny A, Starosławska E, Budny B, et al.
[Epidemiology and diagnosis of breast cancer].
Pol Merkur Lekarski. 2019; 46(275):195-204 [PubMed] Related Publications
Breast cancer is the most common cancer in women. Family history of breast cancer, age at menarche, number of pregnancies and births, history of breast biopsies, use of hormone replacement therapy and time from the last menstrual period are the key events to note. In addition, a high percentage of cases has been demonstrated in women with a genetically conditioned cancer, i.e. mutations in genes BRCA1, BRCA2, syndromes of Li-Fraumeni, Cowden and Peutz-Jeghers. Over 90% of cases are local or regional when detected. The diagnostics approach consists of self-control, breast palpation by the doctor, breast imaging usually with ultrasound, mammography and magnetic resonance. To confirm the diagnosis, a fine-, core-needle or mammotome biopsy is performed. The final diagnosis is based on a wide panel of immunohistochemical and cytogenetic tests. Histological examination provides accurate assessment of the tumor type, grade, estrogen and progesterone hormone receptor status, HER2 overexpression and Ki67 proliferation index. The data makes possible to qualify to one of four groups of breast cancer biological subtypes, which allows individualized treatment of the patient.

Stasenko M, Cybulska P, Feit N, et al.
Brain metastasis in epithelial ovarian cancer by BRCA1/2 mutation status.
Gynecol Oncol. 2019; 154(1):144-149 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
OBJECTIVE: To evaluate clinical outcomes of patients with BRCA-associated ovarian cancer who developed brain metastases (BM).
METHODS: Patients with epithelial ovarian, fallopian tube, and primary peritoneal cancer (EOC) and BM, treated at a single institution from 1/1/2008-7/1/2018, were identified from two institutional databases. Charts and medical records were retrospectively reviewed for clinical characteristics and germline BRCA mutation status. Appropriate statistics were used.
RESULTS: Of 3649 patients with EOC, 91 had BM (2.5%). Germline mutation status was available for 63 (69%) cases; 21 (35%) of these harbored a BRCA1/2 mutation (15 BRCA1, 6 BRCA2). Clinical characteristics were similar between groups. BM were diagnosed at a median of 31 months (95% CI, 22.6-39.4) in BRCA-mutated (mBRCA) and 32 months (95% CI, 23.7-40.3) in wild-type BRCA (wtBRCA) (p = 0.78) patients. Brain metastases were the only evidence of disease at time of BM diagnoses in 48% (n = 10) mBRCA and 19% (n = 8) wtBRCA (p = 0.02) patients. There was no difference in treatment of BM by mutation status (p = 0.84). Survival from time of BM diagnosis was 29 months (95%CI, 15.5-42.5) in mBRCA and 9 months (95% CI, 5.5-12.5) in wtBRCA patients, with an adjusted hazard ratio (HR) of 0.53, p = 0.09; 95% CI, 0.25-1.11. HR was adjusted for presence of systemic disease at time of BM diagnosis.
CONCLUSION: This is the largest study to date comparing outcomes in patients with EOC and BM by mutation status. mBRCA patients were more likely to have isolated BM, which may be a factor in their long survival. This supports the pursuit of aggressive treatment for mBRCA EOC patients with BM. Additional studies examining the correlation of BRCA mutational status with BM are warranted.

Nikolopoulou A, Galli-Vareia I, Stravodimou A, et al.
[New therapeutic strategies in advanced stage breast and tubo-ovarian cancers].
Rev Med Suisse. 2019; 15(651):1027-1031 [PubMed] Related Publications
New targeted therapies modify therapeutic strategies for advanced stage breast and tubo-ovarian cancers. Chemotherapy and endocrine therapy remain the cornerstones of breast cancer treatment. Inhibitors of CDK4/6, mTOR and PI3K are associated with endocrine therapy to increase its effectiveness. PARP inhibitors outperform chemotherapy in BRCA1/2 mutation carriers. Immunotherapy integrates into the treatment of triple-negative cancers with very promising results. For tubo-ovarian cancers, the concept of « platinum-sensitive » has been tempered since the arrival of antiangiogenic treatment and PARP inhibitors that prolong the disease control not only in patients with BRCA1/2 mutation, but also in others.

Toss A, Molinaro E, Sammarini M, et al.
Hereditary ovarian cancers: state of the art.
Minerva Med. 2019; 110(4):301-319 [PubMed] Related Publications
The identification of a mutation in ovarian cancer (OC) predisposition genes plays a crucial role in the management of cancer prevention, diagnosis, and treatment. In healthy carriers, the detection of a specific mutation might justify more intensive and personalised surveillance programmes, chemopreventive measures, and prophylactic surgeries. Moreover, the identification of a mutation in affected OC patients might provide fundamental knowledge of the tumour pathogenesis, thus guiding treatment choices. This is a comprehensive review of the molecular pathways involved in the pathogenesis of hereditary ovarian cancers, the clinical-pathological features of these tumours, and the potential implications for their prevention and clinical management.

Giampaolino P, Della Corte L, Foreste V, et al.
Unraveling a difficult diagnosis: the tricks for early recognition of ovarian cancer.
Minerva Med. 2019; 110(4):279-291 [PubMed] Related Publications
Epithelial ovarian cancer (EOC) is the predominant type of ovarian cancer (OC). The 5-year survival of patients has improved over the last three decades, although the overall cure rate of OC if about 30%. Despite high response rates after initial chemotherapy, most patients with advanced ovarian cancer ultimately develop the recurrent disease because of resistance to chemotherapy. A proper early diagnosis and treatment of patients with ovarian cancer are urgently needed. Nowadays the diagnosis is performed by means of clinical symptoms and signs, often indicators of a disease already at an advanced stage, tumor markers (CA125 and HE4), transvaginal ultrasonography and imaging, very useful in distinguishing adnexal masses. Understand the nature of an adnexal mass is the primary point to begin the diagnosis of OC. Validated different model to approach and characterize adnexal pathology preoperatively are described, such as the International Ovarian Tumor Analysis (IOTA) and the Assessment of Different NEoplasias in the AdneXa (ADNEX) model. New tumor markers, such as PRSS8, FOLR1, KLK6/7, GSTT1, and miRNAs, are getting ahead and are worth noting for early detection of ovarian cancer. Despite the development of numerous ultrasound models for the diagnosis of adnexal masses and the analysis of different tumor markers, the early diagnosis of ovarian cancer is still difficult to practice. Moreover, identifying genetic risk alleles, such as germline BRCA1 and BRCA2 mutations, for ovarian cancer has had a significant impact on disease prevention strategies.

Tomao F, Musacchio L, Di Mauro F, et al.
Is BRCA mutational status a predictor of platinum-based chemotherapy related hematologic toxicity in high-grade serous ovarian cancer patients?
Gynecol Oncol. 2019; 154(1):138-143 [PubMed] Related Publications
OBJECTIVE: To evaluate hematologic adverse effect profiles associated with frontline platinum-based chemotherapy in ovarian cancer patients according to BRCA 1/2 mutational status.
METHODS: Patients with high-grade serous ovarian cancer and a known BRCA mutational status who received in frontline 6 cycles of Carboplatin (AUC 5) plus Paclitaxel 175 mg/mq were retrospectively selected from our databases. Hematologic toxicity profiles of BRCA mutated patients were compared to non-mutated patients, according to EORTC Common Terminology Criteria for Adverse Events (CTCAE_4.02).
RESULTS: Totally, 176 women of whom 58 (33%) were BRCA1/2 mutation carriers - 40 BRCA1 (69%) and 18 (31%) BRCA2 mutations carriers - and 118 (67%) non-carriers were identified. A significant higher frequency of thrombocytopenia (24% vs 5%; p < 0.001), anemia (21% vs 7%; p = 0.006) and neutropenia (62% vs 27%; p ≤0.001) was observed in BRCA mutated patients, resulting in a higher percentage of granulocyte-colony stimulating growth factors injection (12% versus 1%, p < 0.001) and dose delay (19% versus 27%, p = 0.005). The multivariate analysis confirmed that granulocyte-colony stimulating growth factors injection and dose delay were statistically significantly more frequent in BRCA mutated patients (OR 2.567, 95% CI 1.136-5.798, p = 0.035; OR 3.860, 95% CI 1.098-13.570, p = 0.023). Finally, the total number of hematologic adverse events compared between the two groups of patients during the entire treatment period showed a substantial higher rate of hematologic adverse events in BRCA mutated population.
CONCLUSIONS: Germline BRCA 1/2 mutations are associated with a higher hematologic toxicity in patients with ovarian cancer who underwent platinum-based chemotherapy.

Zakrzewski F, Gieldon L, Rump A, et al.
Targeted capture-based NGS is superior to multiplex PCR-based NGS for hereditary BRCA1 and BRCA2 gene analysis in FFPE tumor samples.
BMC Cancer. 2019; 19(1):396 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: With the introduction of Olaparib treatment for BRCA-deficient recurrent ovarian cancer, testing for somatic and/or germline mutations in BRCA1/2 genes in tumor tissues became essential for treatment decisions. In most cases only formalin-fixed paraffin-embedded (FFPE) samples, containing fragmented and chemically modified DNA of minor quality, are available. Thus, multiplex PCR-based sequencing is most commonly applied in routine molecular testing, which is predominantly focused on the identification of known hot spot mutations in oncogenes.
METHODS: We compared the overall performance of an adjusted targeted capture-based enrichment protocol and a multiplex PCR-based approach for calling of pathogenic SNVs and InDels using DNA extracted from 13 FFPE tissue samples. We further applied both strategies to seven blood samples and five matched FFPE tumor tissues of patients with known germline exon-spanning deletions and gene-wide duplications in BRCA1/2 to evaluate CNV detection based solely on panel NGS data. Finally, we analyzed DNA from FFPE tissues of 11 index patients from families suspected of having hereditary breast and ovarian cancer, of whom no blood samples were available for testing, in order to identify underlying pathogenic germline BRCA1/2 mutations.
RESULTS: The multiplex PCR-based protocol produced inhomogeneous coverage among targets of each sample and between samples as well as sporadic amplicon drop out, leading to insufficiently or non-covered nucleotides, which subsequently hindered variant detection. This protocol further led to detection of PCR-artifacts that could easily have been misinterpreted as pathogenic mutations. No such limitations were observed by application of an adjusted targeted capture-based protocol, which allowed for CNV calling with 86% sensitivity and 100% specificity. All pathogenic CNVs were confirmed in the five matched FFPE tumor samples from patients carrying known pathogenic germline mutations and we additionally identified somatic loss of the second allele in BRCA1/2. Furthermore we detected pathogenic BRCA1/2 variants in four the eleven FFPE samples from patients of whom no blood was available for analysis.
CONCLUSIONS: We demonstrate that an adjusted targeted capture-based enrichment protocol is superior to commonly applied multiplex PCR-based protocols for reliable BRCA1/2 variant detection, including CNV-detection, using FFPE tumor samples.

Ledermann JA
Do increased tumor infiltrating lymphocytes co-existing with Homologous Recombination Deficiency provide clues to enhance immunotherapy of ovarian cancer?
Gynecol Oncol. 2019; 153(2):213-214 [PubMed] Related Publications

Lu L, Huang H, Zhou J, et al.
BRCA1 mRNA expression modifies the effect of T cell activation score on patient survival in breast cancer.
BMC Cancer. 2019; 19(1):387 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
METHODS: The interactions between T cell activation status and either BRCA1 or CCND1 expression were evaluated using Kaplan-Meier survival curves and multivariate Cox regression models in a public dataset with 1088 breast cancer patients.
RESULTS: Among the patients with low BRCA1 or CCND1 expression, the Activation group showed better overall survival than the Exhaustion group. Adjusted hazards ratios were 0.43 (95% CI: 0.20-0.93) in patients with a low BRCA1 level, and 0.39 (95% CI: 0.19-0.81) in patients with a low CCND1 level, respectively. There was a significant trend in both subgroups (p-trend = 0.011 in the low BRCA1 group, and p-trend = 0.009 in the low CCND1 group). In contrast, there is no significant association in patients with either high BRCA1 or high CCND1 levels. There is a significant interaction between T cell activation status and BRCA1 level (p = 0.009), but not between T cell activation status and CCND1 level (p = 0.135).
CONCLUSIONS: BRCA1 expression modified the effect of T cell activation status on patient survival in breast cancer, suggesting that the existence of neoantigens and the enhancement of neoantigen presentation in combination with immune checkpoint blockade may have synergistic effects on patient outcome.

Chen X, Chen F, Ren Y, et al.
IL-6 signaling contributes to radioresistance of prostate cancer through key DNA repair-associated molecules ATM, ATR, and BRCA 1/2.
J Cancer Res Clin Oncol. 2019; 145(6):1471-1484 [PubMed] Related Publications
PURPOSE: To study an association between IL-6 signaling and resistance to radiotherapy of prostate cancer (PCa) and explore the molecular mechanisms involved.
METHODS: IL-6 expressing C4-2 and CWR22Rv1 (C4-2IL-6/CWRIL-6) and vector control (C4-2vec/CWRvec) cell lines were developed. Radiation-sensitivities of these cells were compared in clonogenic assay, Comet assay, and γH2AX staining. In xenograft animal studies, radiation-sensitivity of C4-2IL-6 cell-derived tumors vs. C4-2vec cell-derived tumors was investigated. To reveal IL-6 downstream molecules involved in DNA repair after radiation, qPCR and Western blot analyses as well as immunofluorescence staining were performed. Transcriptional control of IL-6 on ATM and ATR molecules was also investigated.
RESULTS: We found C4-2IL-6 and CWRIL-6 cells survived better than their vector control cells after irradiation, and animal studies confirmed such in vitro results. We discovered that DNA repair-related molecules such as ATM, ATR, BRCA1, and BRCA2 were significantly upregulated in irradiated IL-6 expressing cells compared with vector control cells. We further defined that IL-6 signaling regulated cellular expressions of ATM and ATR at the transcriptional level through the activation of Stat3 signaling pathway.
CONCLUSIONS: IL-6 leads to PCa resistance to radiation through upregulation of DNA repair associated molecules ATM, ATR, BRCA1, and BRCA2.

Gulhan DC, Lee JJ, Melloni GEM, et al.
Detecting the mutational signature of homologous recombination deficiency in clinical samples.
Nat Genet. 2019; 51(5):912-919 [PubMed] Related Publications
Mutations in BRCA1 and/or BRCA2 (BRCA1/2) are the most common indication of deficiency in the homologous recombination (HR) DNA repair pathway. However, recent genome-wide analyses have shown that the same pattern of mutations found in BRCA1/2-mutant tumors is also present in several other tumors. Here, we present a new computational tool called Signature Multivariate Analysis (SigMA), which can be used to accurately detect the mutational signature associated with HR deficiency from targeted gene panels. Whereas previous methods require whole-genome or whole-exome data, our method detects the HR-deficiency signature even from low mutation counts, by using a likelihood-based measure combined with machine-learning techniques. Cell lines that we identify as HR deficient show a significant response to poly (ADP-ribose) polymerase (PARP) inhibitors; patients with ovarian cancer whom we found to be HR deficient show a significantly longer overall survival with platinum regimens. By enabling panel-based identification of mutational signatures, our method substantially increases the number of patients that may be considered for treatments targeting HR deficiency.

Yan T, Cui H, Zhou Y, et al.
Multi-region sequencing unveils novel actionable targets and spatial heterogeneity in esophageal squamous cell carcinoma.
Nat Commun. 2019; 10(1):1670 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Esophageal squamous cell carcinoma (ESCC) ranks fourth among cancer-related deaths in China due to the lack of actionable molecules. We performed whole-exome and T-cell receptor (TCR) repertoire sequencing on multi-regional tumors, normal tissues and blood samples from 39 ESCC patients. The data revealed 12.8% of ERBB4 mutations at patient level and functional study supported its oncogenic role. 18% of patients with early BRCA1/2 variants were associated with high-level contribution of signature 3, which was validated in an independent large cohort (n = 508). Furthermore, knockdown of BRCA1/2 dramatically increased sensitivity to cisplatin in ESCC cells. 5% of patients harbored focal high-level amplification of CD274 that led to massive expression of PD-L1, and might be more sensitive to immune checkpoint blockade. Finally, we found a tight correlation between genomic and TCR repertoire intra-tumor heterogeneity (ITH). Collectively, we reveal high-level ITH in ESCC, identify several potential actionable targets and may provide novel insight into ESCC treatment.

Senel M, Dervisevic M, Kokkokoğlu F
Electrochemical DNA biosensors for label-free breast cancer gene marker detection.
Anal Bioanal Chem. 2019; 411(13):2925-2935 [PubMed] Related Publications
We present an electrochemical DNA detection strategy based on self-assembled ferrocene-cored poly(amidoamine) dendrimers for the detection of a gene relevant to breast cancer. The chemisorption of three ferrocene-cored poly(amidoamine) generations and hybridization of single-stranded DNA on a Au electrode were studied by cyclic voltammetry and differential pulse voltammetry. The biosensor demonstrated high sensitivity of 0.13 μA/(ng/ml) in the detection of the target DNA with a linear range of 1.3-20 nM and a detection limit of 0.38 nM. The DNA biosensor also has high selectivity for the target DNA, showing a clear signal difference from a noncomplementary sequence and a single-base-mismatch sequence, which was used as a model of BRAC1 gene mutation. The results shown are highly motivating for exploring DNA biosensing technology in the diagnosis of breast cancer caused by mutation of the BRAC1 gene. Graphical abstract.

Molfino A, Amabile MI, Lionetto L, et al.
DHA Oral Supplementation Modulates Serum Epoxydocosapentaenoic Acid (EDP) Levels in Breast Cancer Patients.
Oxid Med Cell Longev. 2019; 2019:1280987 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Introduction: The omega-3 polyunsaturated fatty acids, as docosahexaenoic acid (DHA), are considered mediators regulating the resolution of inflammation during cancer and may be associated with better outcomes. Epoxydocosapentaenoic acids (EDPs), metabolites of the DHA, are hypothesized to be responsible for some beneficial effects. In the present study, we aimed to assess the circulating 19,20-EDP levels in breast cancer (BC) patients and in healthy controls before and after DHA oral supplementation and the potential differences in the DHA conversion in 19,20-EDPs between patients with different BC presentations.
Methods: BC patients and healthy controls were supplemented with DHA (algal oil) for 10 days (2 g/day). Blood samples were collected at baseline (T0) and after supplementation (T1) to assess EDP (19,20-EDP) serum levels by liquid chromatography spectrometry.
Results: 33 BC patients and 10 controls were studied. EDP values at T0 were not different between patients and controls. At T1, we found an increase in 19,20-EDP levels in BC patients (
Conclusions: DHA oral supplementation was associated with increased 19,20-EDP serum levels in BC patients, independent of the type of BC presentation, and in controls. Patients carrier of BRCA1/2 mutation seem to possess lower ability of DHA epoxidation, whereas luminal A-like BC patients showed higher EDP conversion. This behavior should be tested in a larger population.

Shahi RB, De Brakeleer S, Caljon B, et al.
Identification of candidate cancer predisposing variants by performing whole-exome sequencing on index patients from BRCA1 and BRCA2-negative breast cancer families.
BMC Cancer. 2019; 19(1):313 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: In the majority of familial breast cancer (BC) families, the etiology of the disease remains unresolved. To identify missing BC heritability resulting from relatively rare variants (minor allele frequency ≤ 1%), we have performed whole exome sequencing followed by variant analysis in a virtual panel of 492 cancer-associated genes on BC patients from BRCA1 and BRCA2 negative families with elevated BC risk.
METHODS: BC patients from 54 BRCA1 and BRCA2-negative families with elevated BC risk and 120 matched controls were considered for germline DNA whole exome sequencing. Rare variants identified in the exome and in a virtual panel of cancer-associated genes [492 genes associated with different types of (hereditary) cancer] were compared between BC patients and controls. Nonsense, frame-shift indels and splice-site variants (strong protein-damaging variants, called PDAVs later on) observed in BC patients within the genes of the panel, which we estimated to possess the highest probability to predispose to BC, were further validated using an alternative sequencing procedure.
RESULTS: Exome- and cancer-associated gene panel-wide variant analysis show that there is no significant difference in the average number of rare variants found in BC patients compared to controls. However, the genes in the cancer-associated gene panel with nonsense variants were more than two-fold over-represented in women with BC and commonly involved in the DNA double-strand break repair process. Approximately 44% (24 of 54) of BC patients harbored 31 PDAVs, of which 11 were novel. These variants were found in genes associated with known or suspected BC predisposition (PALB2, BARD1, CHEK2, RAD51C and FANCA) or in predisposing genes linked to other cancer types but not well-studied in the context of familial BC (EXO1, RECQL4, CCNH, MUS81, TDP1, DCLRE1A, DCLRE1C, PDE11A and RINT1) and genes associated with different hereditary syndromes but not yet clearly associated with familial cancer syndromes (ABCC11, BBS10, CD96, CYP1A1, DHCR7, DNAH11, ESCO2, FLT4, HPS6, MYH8, NME8 and TTC8). Exome-wide, only a few genes appeared to be enriched for PDAVs in the familial BC patients compared to controls.
CONCLUSIONS: We have identified a series of novel candidate BC predisposition variants/genes. These variants/genes should be further investigated in larger cohorts/case-control studies. Other studies including co-segregation analyses in affected families, locus-specific loss of heterozygosity and functional studies should shed further light on their relevance for BC risk.

Wang L, Wang H, Wang T, et al.
Analysis of polymorphisms in genes associated with the FA/BRCA pathway in three patients with multiple primary malignant neoplasms.
Artif Cells Nanomed Biotechnol. 2019; 47(1):1101-1112 [PubMed] Related Publications
Cases of more than three primary cancers are very rare. This study analyzed the genetic susceptibility of gene polymorphisms in three patients with multiple primary malignant neoplasms and examined the possible pathogenesis. The clinical data and whole genome sequence of three patients (1 with 5 primary cancers, 1 with 4 primary cancers, and 1 with 3 primary cancers) were aligned with a series of databases. We found the three patients contained a total of seven types of malignant tumours (endometrial cancer, ovarian cancer, breast cancer, colon cancer, ureter cancer, bladder cancer and kidney cancer). It was found that the varied genes in Patient 1 (5 primary cancers) were BRIP1, FANCG, NBN, AXIN2, SRD5A2, and CEBPA. Patient 2 (4 primary cancers) had variations in the following genes: BMPR1A, FANCD2, MLH3, BRCA2, and FANCM. Patient 3 (3 primary cancers) had variations in the following genes: MEN1, ATM, MSH3, BRCA1, FANCL, CEBPA, and FANCA. String software was used to analyze the KEGG pathway of the variations in these three samples, which revealed that the genes are involved in the Fanconi anaemia pathway. Defects in DNA damage repair may be one of the causes of multiple primary cancers.

Laufer-Amorim R, Fonseca-Alves CE, Villacis RAR, et al.
Comprehensive Genomic Profiling of Androgen-Receptor-Negative Canine Prostate Cancer.
Int J Mol Sci. 2019; 20(7) [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Canine carcinomas have been considered natural models for human diseases; however, the genomic profile of canine prostate cancers (PCs) has not been explored. In this study, 14 PC androgen-receptor-negative cases, 4 proliferative inflammatory atrophies (PIA), and 5 normal prostate tissues were investigated by array-based comparative genomic hybridization (aCGH). Copy number alterations (CNAs) were assessed using the Canine Genome CGH Microarray 4 × 44K (Agilent Technologies). Genes covered by recurrent CNAs were submitted to enrichment and cross-validation analysis. In addition, the expression levels of

Adamovich AI, Banerjee T, Wingo M, et al.
Functional analysis of BARD1 missense variants in homology-directed repair and damage sensitivity.
PLoS Genet. 2019; 15(3):e1008049 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
The BARD1 protein, which heterodimerizes with BRCA1, is encoded by a known breast cancer susceptibility gene. While several BARD1 variants have been identified as pathogenic, many more missense variants exist that do not occur frequently enough to assign a clinical risk. In this paper, whole exome sequencing of over 10,000 cancer samples from 33 cancer types identified from somatic mutations and loss of heterozygosity in tumors 76 potentially cancer-associated BARD1 missense and truncation variants. These variants were tested in a functional assay for homology-directed repair (HDR), as HDR deficiencies have been shown to correlate with clinical pathogenicity for BRCA1 variants. From these 76 variants, 4 in the ankyrin repeat domain and 5 in the BRCT domain were found to be non-functional in HDR. Two known benign variants were found to be functional in HDR, and three known pathogenic variants were non-functional, supporting the notion that the HDR assay can be used to predict the clinical risk of BARD1 variants. The identification of HDR-deficient variants in the ankyrin repeat domain indicates there are DNA repair functions associated with this domain that have not been closely examined. In order to examine whether BARD1-associated loss of HDR function results in DNA damage sensitivity, cells expressing non-functional BARD1 variants were treated with ionizing radiation or cisplatin. These cells were found to be more sensitive to DNA damage, and variations in the residual HDR function of non-functional variants did not correlate with variations in sensitivity. These findings improve the understanding of BARD1 functional domains in DNA repair and support that this functional assay is useful for predicting the cancer association of BARD1 variants.

Verma S, Yeddula N, Soda Y, et al.
BRCA1/BARD1-dependent ubiquitination of NF2 regulates Hippo-YAP1 signaling.
Proc Natl Acad Sci U S A. 2019; 116(15):7363-7370 [PubMed] Article available free on PMC after 27/09/2019 Related Publications
Coordination of growth and genomic stability is critical for normal cell physiology. Although the E3 ubiquitin ligase BRCA1 is a key player in maintenance of genomic stability, its role in growth signaling remains elusive. Here, we show that BRCA1 facilitates stabilization of YAP1 protein and turning "off" the Hippo pathway through ubiquitination of NF2. In BRCA1-deficient cells Hippo pathway is "turned On." Phosphorylation of YAP1 is crucial for this signaling process because a YAP1 mutant harboring alanine substitutions (Mt-YAP5SA) in LATS1 kinase recognition sites not only resists degradation but also rescues YAP1 transcriptional activity in BRCA1-deficient cells. Furthermore, an ectopic expression of the active Mt-YAP5SA, but not inactive Mt-YAP6SA, promotes EGF-independent proliferation and tumorigenesis in BRCA1

Oki T, Sugimoto T, Ogawa M, et al.
[A Case of Early-Onset Breast Cancer for Which the Operative Indication for Breast Conservation Was Based on BRCA Genetic Testing].
Gan To Kagaku Ryoho. 2019; 46(3):555-557 [PubMed] Related Publications
We report a case of a patient with early-onset breast cancer who decided to undergo adaptation for breast-conserving surgery based on the results of genetic testing. A 25-year-old woman became aware of a lump in her left breast and visited a nearby hospital, where she was diagnosed with breast cancer. She has no personal history. Her paternal grandfather was diagnosed with rectal cancer at age 60. Ultrasonography revealed an irregularly-shaped hypoechoic mass measuring 3.8 cm in the C area of her left breast and an enlarged lymph node 2.0 cm in diameter in the left axillary area. The breast tumor was pathologically diagnosed as invasive ductal carcinoma by core needle biopsy and was immunohistochemically characterized as ER(-), PgR(-), and HER2(-), s o-called triple negative. Moreover, lymph node metastasis was confirmed by fine needle aspiration cytology. She underwent neoadjuvant chemotherapy and achieved a clinical complete response. A woman with early-onset triple negative breast cancer has a high probability of hereditary breast and ovarian cancer, with a high risk of ipsilateral second breast cancer after conserving surgery. Thus, BRCA genetic testing may be necessary before surgery. As no pathogenic mutation wasfound in BRCA 1/2 in this case, the patient underwent breast-conserving surgery followed by radiation therapy for the conserved breast. The patient remained healthy and without any recurrence 4 years and 2 months after surgery.

Lheureux S, Gourley C, Vergote I, Oza AM
Epithelial ovarian cancer.
Lancet. 2019; 393(10177):1240-1253 [PubMed] Related Publications
Epithelial ovarian cancer generally presents at an advanced stage and is the most common cause of gynaecological cancer death. Treatment requires expert multidisciplinary care. Population-based screening has been ineffective, but new approaches for early diagnosis and prevention that leverage molecular genomics are in development. Initial therapy includes surgery and adjuvant therapy. Epithelial ovarian cancer is composed of distinct histological subtypes with unique genomic characteristics, which are improving the precision and effectiveness of therapy, allowing discovery of predictors of response such as mutations in breast cancer susceptibility genes BRCA1 and BRCA2, and homologous recombination deficiency for DNA damage response pathway inhibitors or resistance (cyclin E1). Rapidly evolving techniques to measure genomic changes in tumour and blood allow for assessment of sensitivity and emergence of resistance to therapy, and might be accurate indicators of residual disease. Recurrence is usually incurable, and patient symptom control and quality of life are key considerations at this stage. Treatments for recurrence have to be designed from a patient's perspective and incorporate meaningful measures of benefit. Urgent progress is needed to develop evidence and consensus-based treatment guidelines for each subgroup, and requires close international cooperation in conducting clinical trials through academic research groups such as the Gynecologic Cancer Intergroup.

Wu J, Mamidi TKK, Zhang L, Hicks C
Integrating Germline and Somatic Mutation Information for the Discovery of Biomarkers in Triple-Negative Breast Cancer.
Int J Environ Res Public Health. 2019; 16(6) [PubMed] Article available free on PMC after 27/09/2019 Related Publications
Recent advances in high-throughput genotyping and the recent surge of next generation sequencing of the cancer genomes have enabled discovery of germline mutations associated with an increased risk of developing breast cancer and acquired somatic mutations driving the disease. Emerging evidence indicates that germline mutations may interact with somatic mutations to drive carcinogenesis. However, the possible oncogenic interactions and cooperation between germline and somatic alterations in triple-negative breast cancer (TNBC) have not been characterized. The objective of this study was to investigate the possible oncogenic interactions and cooperation between genes containing germline and somatic mutations in TNBC. Our working hypothesis was that genes containing germline mutations associated with an increased risk developing breast cancer also harbor somatic mutations acquired during tumorigenesis, and that these genes are functionally related. We further hypothesized that TNBC originates from a complex interplay among and between genes containing germline and somatic mutations, and that these complex array of interacting genetic factors affect entire molecular networks and biological pathways which in turn drive the disease. We tested this hypothesis by integrating germline mutation information from genome-wide association studies (GWAS) with somatic mutation information on TNBC from The Cancer Genome Atlas (TCGA) using gene expression data from 110 patients with TNBC and 113 controls. We discovered a signature of 237 functionally related genes containing both germline and somatic mutations. We discovered molecular networks and biological pathways enriched for germline and somatic mutations. The top pathways included the hereditary breast cancer and role of

Abdulrashid K, AlHussaini N, Ahmed W, Thalib L
Prevalence of BRCA mutations among hereditary breast and/or ovarian cancer patients in Arab countries: systematic review and meta-analysis.
BMC Cancer. 2019; 19(1):256 [PubMed] Article available free on PMC after 27/09/2019 Related Publications
BACKGROUND: To systematically assess the prevalence of BRCA1 and BRCA2 gene mutations in women with Hereditary Breast and/or Ovarian Cancer (HBOC) in Arab countries and to describe the variability in the BRCA gene mutations in different regions of the Arab world.
METHODS: Observational studies reporting prevalence of BRCA mutations from 22 Arab countries were systematically searched in databases including PUBMED, EMBASE, Web of Science, and Google Scholar. Two reviewers independently screened the studies and extracted data and assessed the risk of bias. Hoy's risk of Bias tool was used to assess the biases in individual studies. Due to substantial heterogeneity, pooled weighted estimates were calculated using Quality Effect Models (QEM) that adjust for bias, while the Random Effect Models (REM) estimates served as the sensitivity estimates.
RESULTS: Fourteen studies reporting prevalence of BRCA were included. The pooled estimate of BRCA among HBOC was 20% (95% CI: 7-36%). Subgroup analysis including only those with low risk of bias provided an estimate of 11% (95% CI: 1-27%). Levant region had higher prevalence 28% (95% CI: 11-49%) compared to Arabian Gulf region and North Africa but differences are not statistically significant, when tested using Z-test for proportions.
CONCLUSION: Given the pooled estimates vary widely with substantial heterogeneity, larger, well-designed studies are warranted to better understand the frequency and the impact of BRCA gene mutations among Arab women.
TRIAL REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD42018095905 .

Blok F, Dasgupta S, Dinjens WNM, et al.
Retrospective study of a 16 year cohort of BRCA1 and BRCA2 carriers presenting for RRSO: Prevalence of invasive and in-situ carcinoma, with follow-up.
Gynecol Oncol. 2019; 153(2):326-334 [PubMed] Related Publications
OBJECTIVES: Carriers of BRCA1 and BRCA2 mutations are at increased risk of high grade serous carcinoma and are therefore offered risk-reducing salpingo-oophorectomy (RRSO) by 40-45 years. Most of these carcinomas are believed to arise in the fallopian tube from serous tubal intraepithelial carcinoma (STIC). We conducted a retrospective study on the prevalence of high grade serous carcinoma and STIC in BRCA1/2 carriers presenting for RRSO, and their follow-up.
METHODS: Consecutive BRCA1/2 carriers presenting for an RRSO at Erasmus MC (2000-2016) were studied. SEE-FIM pathology protocol was followed from 2010 onwards. For the cases with carcinoma and/or STIC, the histology was reviewed and immunohistochemistry (p53 & MIB-1) was performed. Next Generation Targeted Sequencing (NGTS) for TP53 mutation was used to establish clonality in 2 cases.
RESULTS: Of the 527 included patients, 68% were BRCA1, 31.6% were BRCA2, and 0.4% carried both mutations. The prevalence of high grade serous carcinoma was 2.3% (12/527); 59% of these were of tubal origin. High grade serous carcinoma was more common in patients operated on after the recommended age (p = 0.03). Isolated STIC was present in 0.8% (4/527). Two BRCA1 carriers with isolated STIC at RRSO developed peritoneal serous carcinoma >7 years later. Identical TP53 mutations in the peritoneal serous carcinoma and the preceding STIC established their clonal origin.
CONCLUSIONS: High grade serous carcinoma is more common in BRCA1/2 carriers presenting for RRSO after the recommended age, and is more often of tubal origin. Longer follow up of patients with STIC at RRSO should be considered.

Voelker R
Quick Uptakes: Taking the Uncertainty Out of Interpreting BRCA Variants.
JAMA. 2019; 321(14):1340-1341 [PubMed] Related Publications

Huang M, Kamath P, Schlumbrecht M, et al.
Identifying disparities in germline and somatic testing for ovarian cancer.
Gynecol Oncol. 2019; 153(2):297-303 [PubMed] Related Publications
OBJECTIVE: Germline mutations occur in approximately 25% of patients with epithelial ovarian cancers while somatic BRCA mutations are estimated at 5-7%. The objectives of this study were to determine the rate of germline and somatic testing in women with ovarian cancer and to identify disparities in testing at a comprehensive cancer center (CCC) and a safety net hospital (SNH).
METHODS: Patients treated for ovarian cancer from 2011 to 2016 were included. Clinicopathologic data were abstracted from the electronic medical records. Logistic regression modeling were performed to calculate odds ratios (OR) and corresponding 95% confidence intervals (95%CI).
RESULTS: Out of 367 women, 55.3% completed germline testing; 27.0% received somatic testing. Women at the CCC were more likely to be tested for germline (60.4% vs 38.1%, p ≤ 0.001) and somatic (34.3% vs 2.4%, p ≤ 0.001) mutations than those at the SNH. Patients with Medicare (aOR = 0.51, 95%CI 0.28-0.94, p = 0.032) or Medicaid (aOR = 0.42, 95%CI 0.18-0.99, p = 0.048) were less likely to receive germline testing than those privately insured. Patients with Medicaid were less likely to receive somatic testing (aOR = 0.15, 95%CI 0.04-0.62, p = 0.009) than those privately insured. Women with disease recurrence had a higher likelihood of being tested for germline (OR = 3.64, 95%CI 1.94-6.83, P < 0.001) and somatic (OR = 7.89, 95%CI 3.41-18.23, p < 0.001) mutations. There was no difference in germline or somatic testing by race/ethnicity.
CONCLUSIONS: Disparities in both germline and somatic testing exist. Understanding and overcoming barriers to testing may improve cancer-related mortality by allowing for more tailored treatments as well as for improved cascade testing.

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