Breast Cancer Susceptibility Gene Research Articles

Pathogenic germline variants in patients with breast cancer: conversations across generations, practices and patients' attitude.

Background: Breast cancer susceptibility genes such as BRCA1, BRCA2, PALB2, CHEK2 and many others are increasingly recognized among our patient population. In addition to their impact on treatment decisions of tested patients themselves, identifying at-risk family members offer opportunities for cancer preventive measures. Methods: This is an observational cross-sectional study of adult breast cancer patients with positive breast-cancer-susceptibility germline variants who received treatment at our institution. Patients with variants of uncertain significance (VUS), or who refused to give consent, were excluded. The data was collected from an eligible sample of breast cancer patients using a structured questionnaire developed by the study team and tested for validity and reliability, as well as a clinical chart review form. Patients were invited to participate in the study during their scheduled oncology clinics visit. Results: 169 patients were enrolled, including 42 (24.9%) with pathogenic/likely pathogenic (P/LP) BRCA1 variants, 84 (49.7%) with BRCA2 and 43 (25.4%) with non-BRCA variants. All patients were female and the mean age was 45 ± 9.9years. Among 140 eligible patients, 104 (74.3%) underwent prophylactic mastectomy, while 79 (59.0%) of 134 eligible patients had prophylactic bilateral salpingo-oophorectomy (BSO). Results were communicated with family members by majority (n = 160, 94.7%), including 642 first degree female relatives, and 286 (44.5%) of them have taken no action. Fear of positive test results, cost of testing, unwillingness to undergo preventive measures, and social stigma were cited as barriers to genetic testing in 54%, 50%, 34% and 15%, respectively. Conclusion: Risk-reducing interventions including mastectomy and BSO were carried by majority of patients with P/LP variants. However, though the rate of communication of genetic testing results with family members was high, proper preventive measures were relatively low. Cost and fear of cancer diagnosis, were the leading causes that prevented cascade testing in our cohort.

Exploring the informational needs and use of information by patients undergoing risk-reducing breast surgery: a qualitative study

ABSTRACT Women with a pathogenic variant in a breast cancer susceptibility gene undergoing a risk-reducing mastectomy have poorly understood informational needs. Information contributes to individuals achieving their full health potential and is essential in informed decision-making. Whilst many women are satisfied with their decision to have risk-reducing surgery, some will experience regret. Informed decision-making may be important in reducing any associated psychological harm. This study aimed to explore satisfaction with information accessed by patients regarding their risk-reducing mastectomy and better understand their informational needs for risk-reducing surgery decision-making Semi-structured interviews were conducted pre- and post-operatively with 22 women undergoing risk-reducing mastectomies for BRCA1/2 pathogenic variants with no breast cancer history at the Nottingham Breast Institute. Inductive thematic analysis was conducted. Four themes were constructed: Sources of information, Informational needs, Uses of information and Impacts of information. A broad spectrum of information sources were used with an apparent hierarchy. Information from clinicians and lived experiences were preferred to written and online sources. Some participants felt their informational needs were met, others found the information contradictory, cancer-focused and jargon filled. Participants required information early enough to be useful. Informational needs differed between individuals which affected the desired format. Participants informational needs were distinct from women with breast cancer undergoing a mastectomy. Encouraging active and informed decision-making could be important to reduce regret and the associated psychological harm some women experience following a risk-reducing mastectomy. This research offers insights into the informational needs of this distinct cohort and recommendations will guide patient information development.

Surgical Decision Making in Genetically High-Risk Women: Quantifying Postoperative Complications and Long-Term Risks of Supplemental Surgery After Risk-Reducing Mastectomy.

Risk-reducing mastectomy (RRM) helps prevent breast cancer in high-risk women but also carries a risk of unanticipated supplemental surgeries. We sought to determine the likelihood of supplemental surgeries following RRM. We performed a retrospective cohort study of female patients with a confirmed germline pathogenic variant (GPV) in a breast cancer susceptibility gene (BRCA1/2, PALB2 and others) who underwent bilateral or contralateral RRM at our institution between 2006 and 2022. Supplemental surgeries were defined as any operation requiring general or local anesthesia performed outside of the initially planned procedure(s). The Kaplan-Meier method was used to estimate the 5-years cumulative incidence of supplemental surgery. Of 560 GPV carriers, RRMs were performed in 258 (46.1%) women. The median age of the cohort was 44 years (interquartile range 37-52 years), with 33 (12.8%) patients undergoing RRM without reconstruction and 225 (87.2%) undergoing RRM with reconstruction. Following surgery, 34 patients (13.2%) developed early (< 30 days) postoperative complications, including infection, hematoma, seroma, loss of the nipple areola complex, flap necrosis, implant exposure and/or prosthesis removal. At a median follow-up of 3.8 years, 94 (36.4%) GPV carriers underwent at least one reoperation. Participants who experienced an early postoperative complication had the highest rate of reoperation (85.3% vs. 29.0%; p < 0.001) and a significantly higher likelihood of multiple additional surgical interventions (41.2% vs. 10.7%; p < 0.001). The 5-years rate of supplemental surgery was 39.2% [95% confidence interval (CI) 32.7-46.5] in the overall cohort and 31.5% (95% CI 24.9-39.3) in patients without an early postoperative complication. Unanticipated supplemental surgeries occur in 40% of GPV carriers following RRM andin nearly one-third of patients without early postoperative complications.

Systematic Minigene-Based Splicing Analysis and Tentative Clinical Classification of 52 CHEK2 Splice-Site Variants.

Disrupted pre-mRNA splicing is a frequent deleterious mechanism in hereditary cancer. We aimed to functionally analyze candidate spliceogenic variants of the breast cancer susceptibility gene CHEK2 by splicing reporter minigenes. A total of 128 CHEK2 splice-site variants identified in the Breast Cancer After Diagnostic Gene Sequencing (BRIDGES) project (https://cordis.europa.eu/project/id/634935) were analyzed with MaxEntScan and subsetted to 52 variants predicted to impact splicing. Three CHEK2 minigenes, which span all 15 exons, were constructed and validated. The 52 selected variants were then genetically engineered into the minigenes and assayed in MCF-7 (human breast adenocarcinoma) cells. Of 52 variants, 46 (88.5%) impaired splicing. Some of them led to complex splicing patterns with up to 11 different transcripts. Thirty-four variants induced splicing anomalies without any trace or negligible amounts of the full-length transcript. A total of 89 different transcripts were annotated, which derived from different events: single- or multi-exon skipping, alternative site-usage, mutually exclusive exon inclusion, intron retention or combinations of the abovementioned events. Fifty-nine transcripts were predicted to introduce premature termination codons, 7 kept the original open-reading frame, 5 removed the translation start codon, 6 affected the 5'UTR (Untranslated Region), and 2 included missense variations. Analysis of variant c.684-2A > G revealed the activation of a non-canonical TG-acceptor site and exon 6 sequences critical for its recognition. Incorporation of minigene read-outs into an ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology)-based classification scheme allowed us to classify 32 CHEK2 variants (27 pathogenic/likely pathogenic and 5 likely benign). However, 20 variants (38%) remained of uncertain significance, reflecting in part the complex splicing patterns of this gene.

Multi-gene panel testing and association analysis in Cypriot breast cancer cases and controls.

Introduction: It is estimated that around 5% of breast cancer cases carry pathogenic variants in established breast cancer susceptibility genes. However, the underlying prevalence and gene-specific population risk estimates in Cyprus are currently unknown. Methods: We performed sequencing on a population-based case-control study of 990 breast cancer cases and 1094 controls from Cyprus using the BRIDGES sequencing panel. Analyses were conducted separately for protein-truncating and rare missense variants. Results: Protein-truncating variants in established breast cancer susceptibility genes were detected in 3.54% of cases and 0.37% of controls. Protein-truncating variants in BRCA2 and ATM were associated with a high risk of breast cancer, whereas PTVs in BRCA1 and PALB2 were associated with a high risk of estrogen receptor (ER)-negative disease. Among participants with a family history of breast cancer, PTVs in ATM, BRCA2, BRCA1, PALB2 and RAD50 were associated with an increased risk of breast cancer. Furthermore, an additional 19.70% of cases and 17.18% of controls had at least one rare missense variant in established breast cancer susceptibility genes. For BRCA1 and PALB2, rare missense variants were associated with an increased risk of overall and triple-negative breast cancer, respectively. Rare missense variants in BRCA1, ATM, CHEK2 and PALB2 domains, were associated with increased risk of disease subtypes. Conclusion: This study provides population-based prevalence and gene-specific risk estimates for protein-truncating and rare missense variants. These results may have important clinical implications for women who undergo genetic testing and be pivotal for a substantial proportion of breast cancer patients in Cyprus.

Genetic Testing in Metastatic Breast Cancer in the USA: A Podcast.

This podcast highlights the importance of genetic testing in patients with metastatic breast cancer, with a specific focus on germline or inherited breast cancer susceptibility gene (BRCA) mutations. In the USA, national guidelines recommend that all patients with recurrent or metastatic breast cancer should be offered genetic testing for germline breast cancer susceptibility gene 1 or 2 (BRCA1 or 2) mutations to identify patients potentially suitable for treatment with a poly(ADP-ribose) polymerase inhibitor. However, a retrospective study indicated that only 43% of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer who may be eligible for genetic testing have undergone germline BRCA1 or 2 testing. Therefore, a large national effort is required to offer genetic testing to more patients with recurrent or metastatic breast cancer. The aim of this podcast is to provide physicians with information to support the early engagement of patients in discussions about genetic testing, and guidance on how to manage patient concerns about the potential implications of testing. Here, a healthcare professional discusses germline genetic testing with a patient advocate and answers questions regarding the importance of testing in patients with metastatic breast cancer. Furthermore, the authors discuss what it means to receive a positive or negative result for a germline BRCA mutation and the impact this may have on the patient and their family members. Overall, the authors emphasize the importance of healthcare professionals providing every patient with metastatic breast cancer with the relevant information about genetic testing so that patients can make informed decisions. Podcast Audio and Infographic available for this article.Podcast Audio and Infographic available for this article.

Radiotherapy versus low-dose tamoxifen following breast-conserving surgery for low-risk and estrogen receptor-positive breast ductal carcinoma in situ: an international open-label randomized non-inferiority trial (TBCC-ARO DCIS Trial)

BackgroundRadiotherapy (RT) following breast-conserving surgery (BCS) is mainly used to decrease the rate of ipsilateral breast tumor recurrence (IBTR) in women with breast ductal carcinoma in situ (DCIS). Recent studies have demonstrated that low-dose tamoxifen significantly reduces IBTR in breast DCIS. Here, we aim to determine whether the administration of low-dose tamoxifen is non-inferior to RT in preventing IBTR in patients with low-risk characteristics of breast DCIS.Methods/designThis is a prospective, international, open-label, randomized, non-inferiority trial. Patients with low-risk clinicopathologic features (> 40 years old, low risk of breast cancer susceptibility gene (BRCA) 1 and BRCA2 mutations, mammographically detected unicentric and non-mass lesions, low- or intermediate-grade without comedo or necrosis, measuring < 2.5 cm with margins ≥ 3 mm, and estrogen receptor-positive status) of DCIS who underwent BCS will be randomized at a 1:1 ratio to either receive tamoxifen (5 mg/day) for 5 years or undergo RT with conventional fractions (50 Gy in 25 fractions) or hypofractionations (40.05 Gy in 15 fractions). Randomization will be stratified by the Taiwan Breast Cancer Consortium. As approximately 5% of patients cannot tolerate the side effects of low-dose tamoxifen and will receive RT, we estimate that 405 patients will be randomized to a low-dose tamoxifen arm and 405 patients to the RT arm, according to a non-inferiority margin within 5% of IBTR difference and 90% β-power noticing non-inferiority. The primary endpoints are breast tumor recurrence, including ipsilateral, regional, contralateral, and distant recurrence of breast DCIS or invasive cancer. The secondary endpoints are overall survival and adverse effects of RT and tamoxifen. Translational studies will also be conducted for this trial.DiscussionThis is the first non-inferiority trial on breast DCIS. This study will provide an important recommendation for clinical physicians on whether to use low-dose adjuvant tamoxifen for patients with low-risk breast DCIS who do not want to receive adjuvant RT.Trial registrationClinicalTrials.gov, ID: NCT04046159, Registered on April 30, 2019.

β-Glucan Regulates Lipopolysaccharide Induced Genotoxic Damage to The Liver through The Induction of BRCA1 Protein Expression.

The present study aims to investigate the role of breast cancer-susceptibility gene 1 (BRCA1) protein in the β-Glucan (βG) molecule mediated regulation of lipopolysaccharide (LPS)-induced liver genotoxicity. In this experimental study, totally, 32 male Swiss Albino mice were randomly divided into 4 equal groups: control (C), LPS-administered (LPS), βG-administered (βG) and βG-pre-administered/LPS-administered (βG+LPS). The βG was injected at the dose of 150 mg/kg/day intraperitoneally (i.p.) for 3 days. A single dose of 4 mg/ kg (i.p.) LPS was administered 24 hours after the last βG injection. BRCA1 expression was determined by western blot analysis and confirmed by quantitative immunofluorescence. Proliferating cell nuclear antigen (PCNA), nuclear factor erythroid 2-related factor (Nrf2) and 8-OHdG protein levels were also determined by the immunofluorescence analysis. The alkaline comet assay was performed. superoxide dismutase (SOD), catalase (CAT) and membrane lipid peroxidation were biochemically measured, and light microscopic histology was evaluated. The BRCA1 expression level was significantly decreased in the LPS group. However, in the βG+LPS group, expression of BRCA1 protein was over 2 folds higher than the control. After the LPS induction, the DNA strand breaks, oxidative DNA lesions and abnormal proliferation of the liver cells were almost entirely suppressed in βG preadministrated animals, indicating the BRCA1 mediated ubiquitination of PCNA and activation of the DNA damage repair pathways. Activation of Nrf2 in the βG+LPS group resulted in an increase in the levels of Nrf2 pathway dependent antioxidant enzymes SOD and CAT, prevented the peroxidation of membrane lipids and maintained the histological architecture of the liver. The results manifested that the βG is a strong inducer of the BRCA1 protein expression in the LPSinduced hepatic stress and the protein constitutes the key component of a βG mediated liver protection against an LPS-induced genotoxic and pathological damage.

Discovery, Synthesis, and Evaluation of Novel Dual Inhibitors of a Vascular Endothelial Growth Factor Receptor and Poly(ADP-Ribose) Polymerase for BRCA Wild-Type Breast Cancer Therapy.

Poly(ADP-ribose) polymerase (PARP) inhibitors have been approved for the treatment of breast cancer (BC) with breast cancer susceptibility (BRCA) gene mutation. Leveraging new synthetic lethal interactions may be an effective way to broaden the indication of PARP inhibitors for BC patients with wild-type BRCA. Vascular endothelial growth factor receptor (VEGFR)-mediated suppression of angiogenesis has been reported to improve the sensitivity of wild-type BRCA cells to PARP inhibitors through synthetic lethality. Herein, we reported the conjugation of a PARP inhibitor with a VEGFR inhibitor pharmacophore to construct dual VEGFR and PARP inhibitors. The most potent compound 14b is identified to exert promising activities against VEGFR and PARP in the nanomolar range and possesses significant in vitro and in vivo antitumor and antimetastasis features. It also presented a favorable pharmacokinetic characteristics in rats with an oral bioavailability of 60.1%. Collectively, 14b may be a promising therapeutic agent of BRCA wild-type BC.

The cost-effectiveness analysis of maintenance olaparib plus Bevacizumab in patients with advanced ovarian cancer: based on the final survival results from PAOLA-1 trial

IntroductionIn 2023, the final PAOLA-1 trial (NCT02477644) survival data were published documenting the benefits of therapy consisting of olaparib plus bevacizumab for patients with advanced ovarian cancer (AOC) as a function of molecular status. In light of these new data, the present study was conducted with the goal of evaluating the cost-effectiveness of olaparib plus bevacizumab for the treatment of the overall AOC patient population and for homologous recombination deficiency (HRD)-positive patients, patients with a breast cancer susceptibility gene (BRCA) mutations, homologous recombination proficiency (HRD)-positive, or patients not harboring BRCA mutations AOC from a US payers perspective.MethodsA Markov state-transition model with a 15-year time horizon was used to evaluate outcomes of patients administered Olaparib plus bevacizumab versus bevacizumab. Life-years (LYs), quality-adjusted LYs (QALYs), and the incremental cost-effectiveness ratio (ICER) values were evaluated in this study in light of a $150,000/QALY of willingness-to-pay (WTP) threshold. The stability of the established model was evaluated through sensitivity analyses.ResultsRelative to bevacizumab alone, Olaparib plus bevacizumab was associated with mean incremental costs and QALYs (LYs) of olaparib plus bevacizumab versus bevacizumab were $293,656 and 1.85 (2.16), $265,668 and 3.34 (4.02), $242,746 and 1.71 (2.06), and $193,792 and 0.97 (1.14) for overall, BRCA mutation-positive, HRD-positive, and HRD-positive BRCA mutation-negative AOC patients, respectively. The corresponding ICER values for these patient subgroups were $158,729 ($136,218), $79,434 ($66,120), $141,636 ($117,747), and $200,595 ($169,733) per QALY (LY) gained Utility value and the price of olaparib were identified in sensitivity analyses as the primary factors influencing these results.ConclusionAt current pricing levels, maintenance treatment with olaparib plus bevacizumab treatment may represent a cost-effective therapeutic option for BRCA mutations and HRD-positive AOC patients in the USA.

Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk

Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P < 2.5 × 10−6): the five known susceptibility genes ATM, BRCA1, BRCA2, CHEK2 and PALB2, together with MAP3K1. Associations were also observed for LZTR1, ATRIP and BARD1 with P < 1 × 10−4. Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2A at exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small.

A comprehensive analysis of Fanconi anemia genes in Chinese patients with high-risk hereditary breast cancer

BackgroundFour Fanconi anemia (FA) genes (BRCA1, BRCA2, PALB2 and RAD51C) are defined as breast cancer (BC) susceptibility genes. Other FA genes have been inconsistently associated with BC. Thus, the role of other FA genes in BC should be explored in specific populations.MethodsMutations in 16 FA genes were screened with a 98-gene panel sequencing assay in a cohort of 1481 Chinese patients with high-risk hereditary BC. The association between mutations and clinicopathological characteristics as well as prognosis was analyzed. The risk of BC in carriers of FA gene mutations was assessed in the Genome Aggregation Database and the Westlake Biobank for Chinese cohort.ResultsA total of 2.57% (38/1481) BC patients were identified who had 12 other FA gene germline mutations. Among them, the most frequently mutated gene was FANCA (8/1481, 0.54%). These 38 patients carried 35 distinct pathogenic/likely pathogenic variants, of which 21 were novel. We found one rare FANCB deleterious variant (c.1327-3dupT) in our cohort. There was a statistically significant difference in lymph node status between FA gene mutation carriers and non-carriers (p = 0.041). We observed a trend that mutation carriers had larger tumor sizes, lower estrogen receptor (ER) and progesterone receptor (PR) positivity rates, and lower 3.5-year invasive disease-free survival (iDFS) and distant recurrence-free survival (DRFS) rates than non-carriers (tumor size > 2 cm: 51.43% vs. 45.63%; ER positivity rates: 51.43% vs. 60.81%; PR positivity rates: 48.57% vs. 55.16%; 3.5-year iDFS rates: 58.8% vs. 66.7%; 3.5-year DRFS rates: 58.8% vs. 68.8%). The frequency of the mutations in FANCD2, FANCM and BRIP1 trended to be higher among BC cases than that in controls (p = 0.055, 0.08 and 0.08, respectively).ConclusionThis study comprehensively estimated the prevalence, clinicopathological characteristics, prognosis and risk of BC associated with deleterious variants in FA genes in Chinese high-risk hereditary BC patients. It enriches our understanding of the role of FA genes with BC.

Liquid chromatography-tandem mass spectrometry for pharmacokinetics evaluation of AZD5305, a selective PARP1 inhibitor, in mice

Poly (ADP-ribose) polymerase (PARP) inhibitors that are effective against ovarian and breast cancers with breast cancer susceptibility gene (BRCA) mutations have undesirable side effects, such as hematological toxicity. AZD5305, a selective PARP1 inhibitor currently in Phase 1/2 clinical trials, may avoid the side effects caused by PARP2. However, the in vivo pharmacokinetic characteristics of AZD5305 and its bioanalytical methods are unknown. Therefore, a method based on liquid chromatography with tandem mass spectroscopy (LC–MS/MS) was developed and validated to quantify AZD5305 in plasma of mice. Optimal chromatographic separation in terms of peak intensity and symmetry was acquired using a 4-µm Polar-RP 80 Å (2.0 × 150 mm) column with ammonium acetate (5 mM) in distilled water–acetonitrile (50:50, v/v). The retention times of AZD5305 and internal standard (IS; olaparib) were 1.82 min and 1.99 min, respectively. Detection was carried out via triple quadrupole mass spectrometry in positive ion mode employing multiple reaction monitoring transitions at m/z 407.0 → 376.0 for AZD5305 and m/z 435.0 → 281.2 for the IS. The LC–MS/MS method was linear in the range 1–1000 ng/mL with a correlation coefficient ≥ 0.990 and showed acceptable values of major parameters including accuracy, precision, and recovery. Additionally, AZD5305 showed high stability under various conditions. The in vivo and in vitro pharmacokinetics of AZD5305 were successfully characterized by employing the validated LC–MS/MS method. A high level of drug exposure and linear pharmacokinetics were observed after intravenous (IV) bolus and oral administration (PO) of AZD5305 at 0.1–1 mg/kg and 0.1–3 mg/kg, respectively. The bioavailability was close to 100%, and the metabolic stability of AZD5305 in hepatic microsomes of mice and humans was very high. These results may contribute to the improvement of PARP inhibitors that are used to treat malignancies originating from BRCA mutations.

Involvement of p.R72P and PIN3 Ins16bp (TP53) Polymorphisms and the I157T (CHEK2) Mutation in Breast Cancer Occurrence in Burkina Faso

Introduction: The TP53 and CHEK2 genes have been described as breast cancer susceptibility genes and some of their polymorphisms have been associated with an increased risk of breast cancer in certain populations.Aim: The objective of this study was to investigate the p.R72P and PIN3 Ins16bp (TP53) polymorphisms and the I157T (CHEK2) mutation developping of breast cancer. Methods: This case-control study had enrolled 144 participants including 65 cases (breast cancer patients) and 79 controls (women without breast abnormalities) in the city of Ouagadougou in Burkina Faso. The DNA was extracted using the method of “salting out” and the genotyping of polymorphisms was performed by ASO-PCR (Allele Specific Oligonucleotides - Polymerase Chain Reaction), conventional PCR and PCR-RFLP (Polymerase Chain Reaction - Restriction Fragment Length Polymorphism) techniques. Results: The heterozygous genotype (RP) of the p.R72P polymorphism of TP53 gene was in the majority in cases (73.85%) and controls (73.42%). Regarding to the PIN3 Ins16bp polymorphism of TP53 gene, the homozygous wild type (A1A1) was the most represented in both cases (53.85%) and controls (60.76%). Concerning the I157T mutation of CHEK2 gene, only one (01) patient was homozygous mutant (TT) and no controls had the mutation. This study found no association between these polymorphisms and the risk of breast cancer occurrence (p.R72P (OR=0.96; 95%IC (0.59-1.56); p=0.471), PIN3 Ins16bp (OR= 1.1; 95%IC (0.61-1.98); p=0.420)). Conclusion: This study showed that the P allele of the p.R72P polymorphism and the wild-type allele (A1) of the PIN3 Ins16bp polymorphism were in the majority. The I157T mutation was very rare. These polymorphisms were not associated with the risk of developing breast cancer in this study.

Global trends in BRCA-related breast cancer research from 2013 to 2022: A scientometric analysis.

Since the mid-2000s, breast cancer incidence among women has slowly increased at about 0.5% per year. In the last three decades, Breast Cancer Susceptibility Gene (BRCA) has been proven to be the crucial gene in encouraging the incidence and development of breast cancer. However, scientometric analysis on BRCA-related breast cancer is in shortage. Thus, to have a clear understanding of the current status and catch up with the hotspots, a scientometric analysis was conducted on specific academic publications collected from the Web of Science (WoS). We searched the Web of Science Core Collection (WoSCC) to procure associated articles as our dataset. Bibliometric, CiteSpace, VOSviewer, and HistCite software were then applied to conduct visual analyses of countries, institutions, journals, authors, landmark articles, and keywords in this research field. A total of 7,266 articles and 1,310 review articles published between 2013 to 2022 were retrieved eventually. The annual output steadily rose year by year and peaked in 2021. The USA led the way in the number of published works, total citations, and collaboration. BreastCancerResearchandTreatment was the most favoured journal in this research field. Narod SA from the University of Toronto produced the most publications. At last, the most prominent keywords were "breast cancer" (n=1,778), "women" (n=1,369), "brca1" (n=1,276), "ovarian cancer" (n=1,259), "risk" (n=1,181), and "mutations" (n=929), which exposed the hotspots within the BRCA domain of breast cancer study. The tendency in the BRCA research field over the past decade was presented by the scientometric analysis. The current research focus is the clinical trials of poly-adenosine diphosphate ribose polymerase inhibitors (PARPi) drugs and their resistance mechanisms.

GCPBayes pipeline: a tool for exploring pleiotropy at thegene level.

Cross-phenotype association using gene-set analysis can help to detect pleiotropic genes and inform about common mechanisms between diseases. Although there are an increasing number of statistical methods for exploring pleiotropy, there is a lack of proper pipelines to apply gene-set analysis in this context and using genome-scale data in a reasonable running time. We designed a user-friendly pipeline to perform cross-phenotype gene-set analysis between two traits using GCPBayes, a method developed by our team. All analyses could be performed automatically by calling for different scripts in a simple way (using a Shiny app, Bash or R script). A Shiny application was also developed to create different plots to visualize outputs from GCPBayes. Finally, a comprehensive and step-by-step tutorial on how to use the pipeline is provided in our group's GitHub page. We illustrated the application on publicly available GWAS (genome-wide association studies) summary statistics datato identify breast cancer and ovarian cancer susceptibility genes. We have shown that the GCPBayes pipeline could extract pleiotropic genes previously mentioned in the literature, while it also provided new pleiotropic genes and regions that are worthwhile for further investigation. We have also provided some recommendations about parameter selection for decreasing computational time of GCPBayes on genome-scale data.

An overview of the research progress of BRCA gene mutations in breast cancer.

The breast cancer susceptibility gene (BRCA) is an important tumor suppressor gene, including BRCA1 and BRCA2, a biomarker that assesses the risk of breast cancer and influences a patient's individualized treatment options. BRCA1/2 mutation (BRCAm) increases the risk of breast cancer. However, breast-conserving surgery is still an option for BRCAm, and prophylactic mastectomy and nipple-sparing mastectomy may also reduce the risk of breast cancer. BRCAm is sensitive to Poly (ADP-ribose) polymerase inhibitor (PARPi) therapy due to specific types of DNA repair defects, and its combination with other DNA damage pathway inhibitors and endocrine therapy and immunotherapy are also used for the treatment of BRCAm breast cancer. The current treatment and research progress of BRCA1/2 mutant breast cancer in this review provides a basis for the individualized treatment of patients with this type of breast cancer.

The APOBEC3B c.783delG Truncating Mutation Is Not Associated with an Increased Risk of Breast Cancer in the Polish Population.

The APOBEC3B gene belongs to a cluster of DNA-editing enzymes on chromosome 22 and encodes an activation-induced cytidine deaminase. A large deletion of APOBEC3B was associated with increased breast cancer risk, but the evidence is inconclusive. To investigate whether or not APOBEC3B is a breast cancer susceptibility gene, we sequenced this gene in 617 Polish patients with hereditary breast cancer. We detected a single recurrent truncating mutation (c.783delG, p.Val262Phefs) in four of the 617 (0.65%) hereditary cases by sequencing. We then genotyped an additional 12,484 women with unselected breast cancer and 3740 cancer-free women for the c.783delG mutation. The APOBEC3B c.783delG allele was detected in 60 (0.48%) unselected cases and 19 (0.51%) controls (OR = 0.95, 95% CI 0.56-1.59, p = 0.94). The allele was present in 8 of 1968 (0.41%) familial breast cancer patients from unselected cases (OR = 0.80, 95% CI 0.35-1.83, p = 0.74). Clinical characteristics of breast tumors in carriers of the APOBEC3B mutation and non-carriers were similar. No cancer type was more frequent in the relatives of mutation carriers than in those of non-carriers. We conclude the APOBEC3B deleterious mutation p.Val262Phefs does not confer breast cancer risk. These data do not support the hypothesis that APOBEC3B is a breast cancer susceptibility gene.

Identification and evaluation of a novel PARP1 inhibitor for the treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a particularly invasive subtype of breast cancer and usually has a poor prognosis due to the lack of effective therapeutic targets. Approximately 25% of TNBC patients carry a breast cancer susceptibility gene1/2 (BRCA1/2) mutation. Clinically, PARP1 inhibitors have been approved for the treatment of patients with BRCA1/2-mutated breast cancer through the mechanism of synthetic lethality. In this study, we identified compound 6 {systematic name: 2-[2-(4-Hydroxy-phenyl)-vinyl]-3H-quinazolin-4-one} as a novel PARP1 inhibitor from established virtual screening methods. Compound 6 exerted stronger PARP1 inhibitory activity and anti-cancer activity as compared to olaparib in BRCA1-mutated TNBC cells and TNBC patient-derived organoids. Unexpectedly, we found that compound 6 also significantly inhibited cell viability, proliferation, and induced cell apoptosis in BRCA wild-type TNBC cells. To further elucidate the underlying molecular mechanism, we found that tankyrase (TNKS), a vital promoter of homologous-recombination repair, was a potential target of compound 6 by cheminformatics analysis. Compound 6 not only decreased the expression of PAR, but also down-regulated the expression of TNKS, thus resulting in significant DNA single-strand and double-strand breaks in BRCA wild-type TNBC cells. In addition, we demonstrated that compound 6 enhanced the sensitivity of BRCA1-mutated and wild-type TNBC cells to chemotherapy including paclitaxel and cisplatin. Collectively, our study identified a novel PARP1 inhibitor, providing a therapeutic candidate for the treatment of TNBC.

Identification of small molecule inhibitors of RAD52 for breast cancer therapy: in silico approach

The breast cancer susceptibility gene 1/2 (BRCA1/2) are the key regulators in maintaining the genomic integrity and mutations in these genes have been associated with development of breast and ovarian cancers. Also, synthetic lethality has been shown in BRCA1/2 deficient cancers, when the RAD52 gene is silenced by shRNA or small molecules aptamers, suggesting a role for RAD52 in the breast cancers pathogenesis. Thus, to find the potential inhibitors of RAD52, a collection of 21,000 compounds from the ChemBridge screening library was screened to conduct molecular docking and molecular dynamics simulation (MD) against RAD52. Further, the results were validated by a density functional theory (DFT) analysis and using post-dynamics free energy calculations. Out of all screened molecules, the docking study revealed five compounds were found to have promising activities against RAD52. Moreover, the catalytic amino acid residues of RAD52 developed stable contacts with compound 8758 and 10593, as anticipated by DFT calculation, MD simulation, and post dynamics MM-GBSA energy calculation. It appears that compound 8758 is the best inhibitor against RAD52 followed by 10593 compared to the other top hits, in terms of the HOMO orbital energy (-1.0966 eV and −1.2136 eV) from DFT and the post dynamics binding free energy calculation (-54.71 and −52.43 Kcal/mol). Furthermore, a drug-like properties of lead molecules (8758 and 10593) were also seen via ADMET analysis. Based on our computational analysis, we hypothesize that a small molecule 8758 and 10593 possess the therapeutic potential in the management for breast cancer patients with a BRCA mutation via targeting RAD52. Communicated by Ramaswamy H. Sarma