BRCA1 Gene Research Articles

Case report: Deciphering the clinical significance of a novel partial BRCA1 exon 10 duplication in a patient with triple-negative breast cancer

Pathogenic/likely pathogenic germline variants in the BRCA1 and BRCA2 genes are associated with an increased risk of developing cancer, particularly breast and/or ovarian tumors. The identification and correct classification of these variants is crucial to find individuals with an increased risk of cancer and to support physicians in their clinical and therapeutic decisions. In addition, the status of BRCA1 and BRCA2 variants is important for appropriate management of patients’ family members. Here, we describe the case of a woman who developed triple-negative breast cancer at the age of 49 years. NGS analysis of BRCA1 and BRCA2 genes revealed the presence of a new partial BRCA1 exon 10 duplication of 2.012 bp. The identified duplication comprises 395 nucleotides from the final portion of intron 9 and 1617 nucleotides from the beginning of exon 10. Using specific primers, we were able to identify the breakpoint at the DNA level and characterize the alteration as a tandem duplication leading to the formation of a premature stop codon after 10 residues. RNA analysis allowed to confirm the production of an altered mRNA showing the duplicated sequence. In this way, we were able to assign a clinical significance to the new alteration and classify it as a pathogenic variant. Although new ClinGen ENIGMA guidelines have been produced to provide tools for the accurate interpretation of variants in the BRCA1 and BRCA2 genes, defining the clinical significance of copy number variants, particularly duplications, remains a challenging goal that requires complex approaches to accurately determine the role of such variants. Other investigations, such as the detection of breakpoints by RNA analysis, are often essential to classify the identified alteration. Our study suggests that RNA transcript analysis is an ideal methodology to support the accurate classification of variants and clarify their effects.

The Current State of Breast Cancer Genetics in Populations of African Ancestry

Breast cancer (BC) constitutes a significant global health burden, particularly among women, with disparities observed across populations. Notably, women of African ancestry often experience BC at earlier ages and in more aggressive forms, with a higher prevalence of metastasis. Genetic studies, including those focused on BRCA1 and BRCA2 genes, have revealed population-specific variations in BC susceptibility. Despite efforts to investigate BC genetics in African and African-descendant populations, research remains limited compared to studies conducted in populations of European descent. Socioeconomic factors further compound the challenges faced by marginalized populations, influencing disease outcomes and treatment efficacy. This review explores the BC literature in African and African-descendant populations, highlighting population-specific genetic variants associated with the disease’s subtypes, treatment response, and disease evolution. Limited sample sizes and lack of data on genetic ancestry hinder the development of precise risk stratification and treatment strategies. Efforts to expand research, improve data collection, and enhance genetic analyses in diverse populations are crucial steps toward addressing racial disparities and advancing BC care on a global scale.

Variants of unknown significance in BRCA1 and BRCA2 among breast cancer patients in Middle Eastern and North African populations: A systematic review

Breast cancer (BC) is a growing global health challenge, particularly in low- and middle-income countries. Variants of unknown significance (VUS) in BC genes, BRCA1 and BRCA2, complicate genetic counseling and treatment decisions, emphasizing the need for reclassification. This systematic review aimed to determine the spectrum of VUS in BRCA1 and BRCA2 among BC patients from the Middle East and North Africa (MENA) region and to evaluate the current understanding and potential reclassification of these variants. A comprehensive search was conducted across electronic databases, including PubMed, Google Scholar, and Embase, for studies published up to early 2024. The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria encompassed studies conducted in the MENA region that focused on BRCA1 and/or BRCA2 in BC and/or ovarian cancer, reported on VUS prevalence, and analyzed coding regions or known mutations. Data extraction was performed using a standardized form, and VUS was reviewed through multiple databases. The review identified 34 eligible studies, with a slight predominance of Middle Eastern studies (n = 18) over North African (n = 16) studies. On reclassification using the ClinVar database, 26% of the VUS were reclassified as benign or likely benign, 34.5% presented conflicting interpretations of pathogenicity, 2% were reclassified as pathogenic or likely pathogenic, and 16.5% remained uncertain. The remaining variants were either not reported or lacked classification. The included studies covered multiple countries in the MENA region, providing insights into the prevalence and characteristics of BRCA1 and BRCA2 VUS in BC patients. The continuous reclassification of VUS is essential for enhancing genetic counseling for BC patients, as it helps clarify the clinical implications of these variants. The findings contribute to understanding the genetic factors in BC susceptibility and may inform clinical practices in genetic counseling and risk assessment in this population.

Prevalence of Somatic BReast CAncer Gene (BRCA) 1 and 2 Pathogenic Variants in Portuguese Metastatic Prostate Cancer Patients

Prevalence of Somatic BReast CAncer Gene (BRCA) 1 and 2 Pathogenic Variants in Portuguese Metastatic Prostate Cancer Patients

Retrospective Study of Genetic Testing Results Reveals Pathogenic Variants Beyond BRCA1/2 in Hereditary Breast and Ovarian Cancer Cases in New Brunswick: Implications for Future Care.

In Canada, founder variants in breast cancer susceptibility genes have been identified in populations residing in Québec and Newfoundland, thus demonstrating the value in characterizing the genetic profile of local populations for better clinical management. New Brunswick has a diverse, yet genetically unexplored population that includes founder Irish and Acadian ancestry, among others, and we hypothesized that this population could demonstrate potential enrichments for variants in breast cancer genes. Health records were retrospectively analyzed for 445 cases referred to the genetics clinic in Moncton, New Brunswick, their molecular results were summarized and compared to allele frequencies from similar studies in Canada. No ethnic or age-related correlation for specific variants could be identified. However, BRCA1/2 variant frequency was lower than expected in the study group and variants in other susceptibility genes such as ATM and CHEK2 were higher when compared to similar studies. This study demonstrates a distinct profile in hereditary breast cancer genetics in a previously uncharacterized population, thus adding to existing knowledge of population genetics in Atlantic Canada.

Genetic mutations and cytotoxic chemotherapy response for advanced solid tumors: A detailed analysis using the C-CAT database in Japan.

130 Background: Chemotherapy regimens are selected based on information about the primary organ or its histological type and are administered based on the results of previous clinical trials. Even now, as cancer genomic research has progressed and precision medicine, which optimizes therapeutic interventions based on tumor genome profiling using next-generation sequencing(NGS), has become standard treatment, cytotoxic anticancer drugs still remain key drugs. We examined the real-world database of genomic and clinical information established by the national central datacenter, the Center for Cancer Genomics and Advanced Therapy (C-CAT) to systematically analyze the effects of mutations across multiple cancers and therapies. Methods: This study delineated the association between genetic mutations and the therapeutic efficacy of cytotoxic chemotherapy in advanced solid tumors in a real-world Japanese clinical context. We incorporated data from 15,474 patients enrolled in the C-CAT database between June 2019 and June 2022. We analyzed the overall response and time to next treatment (TNT) for genetic alterations and five categories of cytotoxic anticancer drugs in gastrointestinal cancers. Results: In the C-CAT data, gastrointestinal cancers were frequently registered, with colorectal cancer being the most common, followed by pancreatic cancer, esophageal/gastric cancer, and biliary tract cancer. For platinum-based drugs, in colorectal cancer, the presence of gene X was associated with not only a higher response rate but also a longer TNT (hazard ratio 0.82, p<0.001). In the case of colorectal cancer and pancreatic cancer with KRAS gene mutations, the ORR was low, and the TNT was also short in the case of pancreatic cancer (hazard ratio 1.33, p<0.001). Interestingly, when BRCA2 genes are mutant, TNT tended to be longer in many organs, suggesting that platinum-based drugs are effective across organs in carcinomas with BRCA2 mutations. Additionally, gene X showed differences in efficacy not only for platinum but also for antimetabolites and topoisomerase inhibitors. Moreover, KRAS mutation was observed in almost all pancreatic cancers and was a treatment-resistant mechanism for all platinum drugs and antimetabolites. Conclusions: This study demonstrated that the effects of cytotoxic anticancer drugs differ depending on genetic mutations. When determining chemotherapy regimens, considering not only the organ but also genetic mutations may enable more efficient drug selection.

Signature of collagen alpha-1(x) gene expression in human cancers and their therapeutic implications.

Cancers are a class of disorders that entail uncontrollably unwanted cell development with dissemination. One in six fatalities globally is attributed to cancer, a global health issue. The analysis of the entire DNA sequence and how it expresses itself in tumor cells is known as cancer genomics. The development of novel cancer treatments has been facilitated because of the genomics method. COL10A1 gene, a short chain collagen, and an interstitial matrix component, acts as a predictive biomarker for cancer prognosis. Recognizing the fundamental consequences of mutations in the COL10A1 gene and its expression in cancer is crucial. Analyzing the COL10A1 gene expression with a data set and gene expression patterns shows the level of display of the tumor. Examining the therapeutic techniques of COL10A1 gene expression leads to early detection, screening, radiation therapy, and advanced developments. This review highlights the value of the COL10A1 gene in breast, gastric, pancreatic, lung, and colorectal cancers, emphasizing its role in gene expression patterns and therapeutic techniques.

Germline pathogenic variants in a cohort of individuals with biliary tract cancer.

559 Background: Biliary tract cancers (BTC) are rare but have been implicated in hereditary cancer conditions such as Lynch syndrome (LS) and BRCA1 and BRCA2. Data from paired somatic and germline genetic testing on BTC have shown that ~5% may be related to germline pathogenic variants in BRCA1 and BRCA2. Identification of these germline pathogenic variants (PV) often provide patients with an opportunity for personalized treatment including platinum-based chemotherapies, PARP inhibitors and/or immunotherapy. Germline testing also provides crucial data to relatives regarding cancer risk and access to increased cancer surveillance and risk-reducing surgeries. Current guidelines recommend germline genetic testing when the likelihood of identifying a PV is >5%. The contribution of germline PV in BTC has not been described in a diverse patient population. Methods: In this prospective clinic-based study, individuals with BTC were referred by their oncologist for genetic counselling and testing. The majority of individuals were enrolled based on participation in the Legresley Biliary Registry, which recruits all individuals with BTC. Blood was sent for germline multi-gene panel testing. Results: Germline genetic testing was performed for 139 individuals. Average age of diagnosis was 57.8 years (range 28-84). The majority of individuals were diagnosed with intrahepatic cholangiocarcinoma (CCA) (54.7%), followed by extrahepatic CCA (20.9%) and gallbladder cancer (10.1%). The majority of individuals were male (56.1%). The population was ethnically diverse with 55% European, 24% Asian, 9% Middle Eastern/North African and 6% African. A minority of individuals had a previous cancer (18%) and 24.5% met current provincial eligibility criteria. Germline testing was complete on 136 individuals. 25/136 (14.7%) PV were identified in 20 individuals. 8/136 (5.9%) of the cohort carried PV in genes known to increase the risk for BTC ( BRCA1, BRCA2 and LS genes), 9/136 (6.6%) carried PV in other genes with clinically actionability (e.g. PALB2, ATM ), and 8/136 (5.9%) carried heterozygous PV in genes for recessive diseases. Variants of uncertain significance were identified in 42/136 (30.9%) and negative results were identified in 74/136 (54.4%). Personal and/or family history was not suggestive of the associated cancer condition in 9/16 (56%) of the PV cohort. Tumor profiling by whole genome sequencing on some individuals with PV found corresponding somatic mutational signatures, consistent with variant pathogenicity. Conclusions: Detection rates for PV in a diverse BTC cohort was up to 14.7%, including 5.9% among genes known to increase the risk for BTC. The majority of PV were found in individuals lacking personal and/or family history suggestive of the associated hereditary cancer condition. These results suggest that guidelines should be updated to recommend universal germline genetic testing for individuals with BTC.

Chronic Exposure to Lead Causes Neurotoxicity by Generating Oxidative Stress and Inducing DNA Damages in Zebrafish Brain: Involvement of Nrf2-Keap1 Regulation and DNA Repair Pathways.

Toxicity of lead (Pb) causes several health problems in human beings. The present study reveals the potential effects of Pb on adult zebrafish (Danio rerio) brain at an environmentally relevant concentration. Pb generated reactive oxygen species-mediated oxidative stress, as evidenced by alterations of GSH, MDA levels, and CAT activity. The Nrf2-Keap1 pathway counteracted this stress as a part of cytoprotection. The gene expression and immunolocalization studies confirmed the augmentation of Nrf2 in the brain. Activation of the Nrf2-Keap1 pathway influenced downstream nqo1 and ho1 gene expressions. The alterations in histopathology and mRNA expressions of biomarker genes like hsp70 and ache revealed the toxic insults of Pb in the brain. DNA damage assay verified the genotoxic potential of Pb. The expression pattern of the candidate genes of two critical repair pathways (base excision and mismatch repair) was studied to assess the DNA damage responses. The damages in DNA caused by 15days of Pb exposure were sufficient to trigger the expression of BER (ogg1, apex1, polβ, and creb1) and MMR (msh2, msh6, and mlh1) genes to protect cells. Chronic exposure for 30days suppressed both the machinery, predisposing mutations. The overexpression of crucial tumor suppressor genes p53 and brca2 indicated their protective role against cancer progression. Understanding the molecular mechanisms underlying Pb-induced neurotoxicity and the DNA damage response may help to improve our current knowledge for the prevention of Pb poisoning.

M6A related metabolic genes in breast cancer and their relationship with prognosis.

Breast cancer (BC) is the most prevalent malignancy among women, with incidence rates rising annually. N6-methyladenosine (m6A) modification has been recognized as a key regulator in the onset and progression of BC. Nevertheless, the role of m6A-associated metabolic genes (mMGs) in BC regulation remains insufficiently understood. In this study, we first analyzed and clustered single-cell transcriptomic (scRNA-seq) data from the peripheral blood of BC patients. Differentially expressed genes (DEGs) across various cell populations were intersected with mMGs to identify differentially expressed mMGs (DEmMGs). The AUCell algorithm was employed to score DEmMGs across cell populations, followed by subgroup clustering of high-scoring cell types. Additionally, DEGs from BC and control transcriptomic (RNA-seq) data in The Cancer Genome Atlas (TCGA) were intersected with DEmMGs. BC subtypes were identified based on the expression levels of overlapping genes, and differences in survival rates and immune microenvironment characteristics were examined across subtypes. A BC risk model was constructed using Lasso-Cox regression, and variations in prognosis, tumor mutational burden, immune cell infiltration, and drug sensitivity were explored. Finally, real-time quantitative PCR (qRT-PCR) and Western blot (WB) were used to validate the identified prognostic genes. NDUFAB1, VDAC1, TYMP, UGDH, ATP6AP1, and ALDH2 showed consistent and significant expression differences between the BC and control groups. This study's identification of key prognostic genes and the development of a risk model offer potential new targets for therapeutic intervention and clinical management of BC.

Identification and validation of a prognostic signature of drug resistance and mitochondrial energy metabolism-related differentially expressed genes for breast cancer

BackgroundDrug resistance constitutes one of the principal causes of poor prognosis in breast cancer patients. Although cancer cells can maintain viability independently of mitochondrial energy metabolism, they remain reliant on mitochondrial functions for the synthesis of new DNA strands. This dependency underscores a potential link between mitochondrial energy metabolism and drug resistance. Hence, drug resistance and mitochondrial energy metabolism-related differentially expressed genes (DMRDEGs) may emerge as candidates for novel cancer biomarkers. This study endeavors to assess the viability of DMRDEGs as biomarkers or therapeutic targets for breast cancer.MethodsWe utilized the DRESIS database and MSigDB to identify genes related to drug resistance. Additionally, we sourced genes associated with mitochondrial energy metabolism from GeneCards and extant literature. By merging these genes with differentially expressed genes observed in normal and tumor tissues from the TCGA-BRCA and GEO databases, we successfully identified the DMRDEGs. Employing unsupervised consensus clustering, we divided breast cancer patients into two distinct groups based on the DMRDEGs. Consequently, we identified four hub genes to formulate a prognostic model, applying Cox regression, LASSO regression, and Random Forest methods. Furthermore, we examined immune infiltration and tumor mutation burden of the genes within our model and scrutinized divergences in the immune microenvironment between high- and low-risk groups. Small hairpin RNA and lentiviral plasmids were designed for stable transfection of breast cancer cell lines MDA-MB-231 and HCC1806. By conducting clone formation, scratch test, transwell assays, cell viability assay and measurement of oxygen consumption we initiated a preliminary investigation into mechanistic roles of AIFM1.ResultsWe utilized DMRDEGs to develop a prognostic model that includes four mRNAs for breast cancer. This model combined with various clinical features and critical breast cancer facets, demonstrated remarkable efficacy in predicting patient outcomes. AIFM1 appeared to enhance the proliferation, migration, and invasiveness of breast cancer cell lines MDA-MB-231 and HCC1806. Moreover, by reducing oxygen consumption, it aids in the cancer cells' acquisition of drug resistance.ConclusionsDMRDEGs hold promise as diagnostic markers and therapeutic targets for breast cancer. Among the associated mutated genes, ATP7B, FUS, AIFM1, and PPARG could serve as early diagnostic indicators, and notably, AIFM1 may present itself as a promising therapeutic target.

Long Intergenic Non-Coding RNAs and BRCA1 in Breast Cancer Pathogenesis: Neighboring Companions or Nemeses?

Breast cancer is one of the leading causes of mortality among women, primarily due to its complex molecular landscape and heterogeneous nature. The tendency of breast cancer patients to develop metastases poses significant challenges in clinical management. Notably, mutations in the breast cancer gene 1 (BRCA1) significantly elevate breast cancer risk. The current research endeavors employ diverse molecular approaches, including RNA, DNA, and protein studies, to explore avenues for the early diagnosis and treatment of breast cancer. Recent attention has shifted towards long non-coding RNAs (lncRNAs) as promising diagnostic, prognostic, and therapeutic targets in the multifaceted progression of breast cancer. Among these, long intergenic non-coding RNAs (lincRNAs), a specific class of lncRNAs, play critical roles in regulating various aspects of tumorigenesis, including cell proliferation, apoptosis, epigenetic modulation, tumor invasion, and metastasis. Their distinctive expression patterns in cellular and tissue contexts underscore their importance in breast cancer development and progression. Harnessing lincRNAs’ sensitivity and precision as diagnostic, therapeutic, and prognostic markers holds significant promise for the clinical management of breast cancer. However, the potential of lincRNAs remains relatively underexplored, particularly in the context of BRCA1-mutated breast cancer and other clinicopathological parameters such as receptor status and patient survival. Consequently, there is an urgent need for comprehensive investigations into novel diagnostic and prognostic breast cancer biomarkers. This review examines the roles of lincRNAs associated with BRCA1 in the landscape of breast cancer, highlighting the potential avenues for future research and clinical applications.

Investigation into drug resistance to cisplatin in cancer stem cell-enriched population in non-small cell lung cancer

Abstract Objectives understanding drug resistance in cancer is of importance in treatment. Cancer stem cells are main factor for drug resistance. Therefore, the possible gene/gene interactions/proteins were explored in our study using a cancer stem cell-enriched population (H1299/S) derived from a parental non-small cell lung cancer cell line (H1299/P). Methods response to cisplatin, which is the main drug for the treatment of lung cancer, was evaluated with the Adenosine triphosphate (ATP) viability test. As a result of the gene expression analysis, while 14 genes were not evaluated, expression profiles were obtained for 37 genes out of 51 genes. By the drug-protein interaction analyses, Topoisomerase I (TOPI), Topoisomerase 2 alpha (TOP2A), Topoisomerase 2 beta (TOP2B), Cyclin-dependent kinases 4 (CDK4), Cyclin-dependent kinases 6 (CDK6), ATP binding cassette subfamily B member 1 (ABCB1), ATP binding cassette subfamily C member 1 (ABCC1), ATP binding cassette subfamily C member 3 (ABCC3), B-cell leukemia/lymphoma 2 (BCL2), Poly (ADP-ribose) polymerase 1 (PARP1), Breast cancer gene 1 (BRCA1) and Cyclin dependent kinase inhibitor 1A (CDKN1A) genes and protein products were statistically significantly found to be in association with drug resistance. Results and discussion in bioinformatics analyses, it was observed that 13 pathways were affected due to expression changes and 12 genes related to these pathways were determined to activate multidrug resistance mechanisms. Conclusions platinum-based drugs, as well as a broad range of other agents including topoisomerase and PARP1 inhibitors, and anthracyclines, have been shown to potentially possess multiple drug resistance.

Unveiling the role of PANoptosis-related genes in breast cancer: an integrated study by multi-omics analysis and machine learning algorithms.

The heterogeneity of breast cancer (BC) necessitates the identification of novel subtypes and prognostic models to enhance patient stratification and treatment strategies. This study aims to identify novel BC subtypes based on PANoptosis-related genes (PRGs) and construct a robust prognostic model to guide individualized treatment strategies. The transcriptome data along with clinical data of BC patients were sourced from the TCGA and GEO databases. Consensus clustering was performed on 12 PRGs to ascertain potential BC subtypes, and variances in survival, infiltration of immune cells, and functional pathways among them were examined. A prognostic model was generated through 101 combinations of machine learning algorithms and validated across multiple cohorts. The response of patients towards immunotherapy were analyzed using multiple frameworks. Consensus clustering of 12 PRGs identified two distinct BC subtypes, with subtype B exhibiting significantly lower overall survival (OS) rates compared to subtype A. Immune cell infiltration analysis revealed higher immune activity in subtype A. Functional pathway analysis revealed that subtype A exhibited a significant enrichment in immune-related pathways, while subtype B was associated with cell cycle and metabolic processes. An integrated machine learning framework integrating CoxBoost and Random Survival Forest (RSF) algorithms was developed, demonstrating high predictive performance across multiple cohorts. A nomogram combining age and risk score was constructed, showing excellent predictive performance. Immune landscape analysis revealed that the high-risk group exhibited a suppressive tumor immune microenvironment (TIME). Immunotherapy response prediction suggested that low-risk patients were more likely to benefit from PD-1 and CTLA-4 inhibitors. Our study provides a comprehensive framework for BC subtype classification and prognostic prediction, offering valuable insights for personalized treatment strategies.

Targeted editing of CCL5 with CRISPR-Cas9 nanoparticles enhances breast cancer immunotherapy.

Breast cancer remains one of the leading causes of cancer-related mortality among women worldwide. Immunotherapy, a promising therapeutic approach, often faces challenges due to the immunosuppressive tumor microenvironment. This study explores the innovative use of CRISPR-Cas9 technology in conjunction with FCPCV nanoparticles to target and edit the C-C Motif Chemokine Ligand 5 (CCL5) gene, aiming to improve the efficacy of breast cancer immunotherapy. Single-cell RNA sequencing (scRNA-seq) and TCGA-BRCA data identified CCL5 as a key immune-related gene in breast cancer. Using CRISPR-Cas9, sgRNA targeting CCL5 was designed and delivered to breast cancer cells and humanized mouse models via FCPCV nanoparticles. In vitro experiments demonstrated that FCPCV nanoparticles effectively silenced CCL5, enhanced CD8+ T cell activity, and increased the production of cytokines such as IFN-γ, TNF-α, and GZMB. In vivo studies revealed significant tumor suppression, improved immune microenvironment, and increased CD8+/CD4+ ratios in treated mice, without notable toxic side effects. These findings highlight the potential of CRISPR-Cas9 nanoparticle-mediated gene editing as a novel strategy for enhancing breast cancer immunotherapy, providing a new direction for personalized and effective cancer treatment.

Effects of photobiomodulation in mitochondrial quantity, biogenesis and mitophagy-associated genes in breast cancer cells.

In this article, we aim to evaluate the effects of photobiomodulation on mitochondria quantity, biogenesis, and mitophagy-associated genes in breast cancer (BC) cells. Both models were irradiated with a low-power infrared laser (880nm, 150 mW) and amber LED (617nm, 1500 mW), alone or simultaneously. We evaluated the mRNA expression of PINK1 and PGC-1α genes, and the mitochondrial number was assessed based on the ratio of mitochondrial DNA/genomic DNA (mtDNA/gDNA). No significant difference was observed in the mtDNA/gDNA ratio comparing the low-power infrared laser (LPIL) and LED-irradiated groups to their control counterparts. Similarly, no difference was observed in the mRNA levels of PINK1 and PGC-1α of the irradiated group with an LPIL and LED alone or in combination. In conclusion, PBM with LPIL and LED did not alter the mtDNA/gDNA ratio nor modulate the mRNA levels of the genes related to mitophagy and biogenesis in BC cells.

Niraparib Maintenance Therapy in Patients with Platinum-Sensitive Recurrent Ovarian Cancer: Real-World Experience at Hospitals in Spain.

The reported benefit of poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance in patients with newly diagnosed and platinum (Pt)-sensitive recurrent ovarian cancer (OC) included in randomized clinical trials needs to be corroborated in a less selected population. The aim is to increase the evidence on niraparib in a real-world setting. This is a retrospective observational study including women with platinum-sensitive relapsed high-grade serous OC who started niraparib maintenance between August 2019 (marketing data, Spain) and May 2022. Patients received ≥ 2 previous lines of therapy with complete or partial response to prior chemotherapy. Patient characteristics, niraparib dose, adequacy of dose individualization, effectiveness (progression-free survival [PFS] and overall survival), safety, and economic savings with an individualized starting dose (ISD) strategy were assessed. The study included 217 patients with a median of 8.9 months of niraparib duration: breast cancer gene (BRCA) wild-type OC, 70%; two prior treatment lines, 49%; Research on Adverse Drug Events and Reports (RADAR) criteria, 82% (receiving mainly 200 mg of niraparib, 79%). Median PFS was 10.8 months (95% confidence interval [CI], 8.4-14.8) without statistically significant differences based on starting dose strategy, contrary to what was observed on the basis of prior lines, response to prior chemotherapy, BRCA mutational status, and International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis. The last three variables also showed a statistically significant predictive prognostic value for effectiveness. Dose interruptions due to toxicity were required in 7% of patients, and dose adjustments in 56% were mainly due to hematologic toxicities. The actual dose of niraparib reveals economic savings versus the theoretical cost. This large real-world analysis corroborates the tolerability and activity of niraparib maintenance for platinum-sensitive recurrent OC and economic savings.

BRCA1 is involved in sustaining rapid antler growth possibly via balancing of the p53/endoplasmic reticulum stress signaling pathway

BackgroundRegeneration is the preferred approach to restore the structure and function after tissue damage. Rapid proliferation of cells over the site of damage is integral to the process of regeneration. However, even subtle mutations in proliferating cells may cause detrimental effects by eliciting abnormal differentiation. Interestingly deer antlers, arguably the fastest regenerating mammalian tissue, have not been reported, thus far, to grow malignant tumors. They provide a mammalian model to understand the possible mechanism by which rapid regeneration is achieved while avoiding the development of malignancies. Antler regeneration is based on the proliferation and differentiation of antler stem cells (AnSCs).ResultsWe identified 39 hub genes which may function in regulating the balance between rapid proliferation and genomic stability in the AnSCs during antler regeneration. Among these 39 genes, the tumor suppressor gene, BRCA1, was found to be more sensitive to DNA damage in the AnSCs compared to that in the deer somatic cells, and BRCA1 deletion in the AnSCs via CRISPR/Cas9 resulted in significantly higher levels of DNA damage. Lack of BRCA1 promoted cell apoptosis and cell senescence and inhibited cell proliferation and cell self-renewal. RNA-seq results showed that in the absence of BRCA1, the p53 signaling pathway was significantly up-regulated. Associated with this change, the cell apoptosis and cell senescence-relevant-genes, CDKN1A, CDKN2A and Fas were over expressed, but the expression of cell-cycle-progression-related genes was inhibited. In addition, BRCA1 expression levels were found to be more sensitive to endoplasmic reticulum stress (ERS) in the AnSCs compared to the somatic cells. Deletion of BRCA1 gene aggravated ERS and ERS-induced cell apoptosis.ConclusionsOur results revealed that BRCA1 is involved in sustaining rapid antler growth possibly via promotion of DNA damage repair that acts to maintain genome stability while protecting cells from p53/ERS-induced cell death. Understanding the mechanisms underlying the role played by BRCA1 in the process of antler regeneration is of great significance not only for regenerative medicine, but also for the understanding of cancer development.

Early Detection of the Pathogenetic Variants of Homologous Recombination Repair Genes in Prostate Cancer: Critical Analysis and Experimental Design

It has been shown that the pathogenic variants (PVs) of the DNA Damage Response (DDR) genes, whether of a germinal or somatic nature, represent a predictive biomarker of high sensitivity to treatment with inhibitors of the enzyme poly-ADP-ribose polymerase (PARP) in patients with hormone-resistant metastatic prostate cancer (HRPCa). Moreover, the detection of PVs of the Homologous Recombination Repair (HRR) genes in PCa patients can help to define the patient’s prognosis and the choice of the therapeutic procedure. Among men with metastatic PCa, the frequency of PVs in HRR genes ranges from 11% to 33%, which is a significantly higher rate compared to non-metastatic PCa, where the incidence is between 5% and 10%. Next-Generation Sequencing (NGS) results were more commonly obtained from newly acquired somatic samples compared to archived samples (prostate biopsy or prostatectomy). We developed an experimental multidisciplinary prospective study in patients with a new diagnosis of high-risk PCa at biopsy. The aim was to evaluate the presence of PVs of different HRR genes in patients with the first diagnosis of PCa in relation to a metastatic or non-metastatic stage, tumor aggressiveness, and early risk of progression. Among 43 initial tumor samples from 22 patients, 25 samples from 12 patients were selected for library preparation based on their DNA concentration and quality. After the NGS, 14 different DNA variants were prioritized. Oncogenetic and likely oncogenetic variants were found in the ATM, BRCA1, PTEN, KMT2D, and CDH1 genes. Moreover, variants of uncertain significance were found in ATM, DDR2, FANCA, FOXA1, PLCB4, PTCH1, and RB1.

Advanced Deep Learning Approaches for Predicting Breast Cancer Genes Using Spectrographic Data

Advanced Deep Learning Approaches for Predicting Breast Cancer Genes Using Spectrographic Data