Search Results (691)

The article presents the current state of knowledge on genetic modifiers of ovarian cancer risk in women carrying pathogenic variants (PVs) in the BRCA1 and BRCA2 genes, which are major contributors to hereditary susceptibility to this malignancy. Although PV carriers have high disease penetrance (BRCA1: ~40% and BRCA2: 11–27%), substantial variability in individual risk is observed, suggesting the influence of additional genetic variants. Background: Ovarian cancer is characterized by late detection and high mortality, and a significant portion of risk among BRCA1/2 carriers is shaped by reproductive and environmental factors as well as genetic modifiers. The article emphasizes that carriers of the same BRCA PV can exhibit markedly different risk levels depending on additional variants that modulate key biological processes, such as DNA repair, cell cycle regulation, and apoptosis. Methods: A systematic literature search covering the years 1996–2025 was conducted in the PubMed database. Initially, 734 publications were identified; after removing duplicates, thematically irrelevant articles, non-full-text papers, and studies not meeting the inclusion criteria, 47 articles were included in the review. These studies covered candidate gene analyses, GWAS, and data from the CIMBA consortium, which enables the examination of large cohorts of PV carriers. Results: The review identified numerous variants associated with increased or decreased ovarian cancer risk in BRCA1 carriers, including the following: OGG1, DR4, MDM2, CYP2A7, CASP8, ITGB3, HRAS1, TRIM61, and MTHFR. The reviewed studies also identified both protective and risk-increasing variants among BRCA2 PV carriers: UNG, TDG, and PARP2, and haplotypes in ATM, BRIP1, BARD1, MRE11, RAD51, and 9p22.2. The analysis identified 11 variants affecting both BRCA1 and BRCA2 carriers, most of which increase risk, including the following: IRS1, RSPO1, SYNPO2, BABAM1, MRPL34, PLEKHM1, and TIPARP. Protective variants include BNC2 and LINC00824. The only SNP reaching genome-wide significance (p < 5 × 10⁻⁸) was in BNC2. Conclusions: The article summarizes the growing number of genetic modifiers of ovarian cancer risk among BRCA1/2 carriers and highlights their potential to improve individualized risk assessment, enhance patient stratification, support personalized prevention and surveillance strategies, deepen the understanding of disease biology, and identify potential therapeutic targets. Full article

Ovarian cancer remains the most lethal gynaecological malignancy primarily due to late-stage diagnosis, high recurrence rate, and limited treatment efficacy. Current diagnostic tools, including imaging and serum markers, lack sufficient sensitivity and specificity for early detection. Increasing evidence highlights the critical role of myeloid-derived immune cells within the tumour microenvironment in shaping ovarian cancer progression and therapy response. Monocytes and their derivatives are central regulators of immune suppression, chemoresistance, and metastatic dissemination in ovarian tumours. Their recruitment and polarisation are governed by several signalling pathways offering promising therapeutic targets. Strategies including monocyte depletion, TAM reprogramming, MDSC maturation, DC vaccines, and their synergistic use with chemotherapy or immune checkpoint inhibitors are being explored to restore anti-tumour immunity in ovarian cancer. Parallel to therapeutic potential, the lymphocyte-to-monocyte ratio and its reciprocal monocyte-to-lymphocyte ratio have also emerged as potential accessible and cost-effective prognostic tools that predict disease aggressiveness and survival in ovarian cancer. This review features the diagnostic, prognostic, and therapeutic significance of monocytes and their derivatives in ovarian cancer management and highlighting new opportunities for next-generation immunomodulatory therapies. Full article

Background: Accurate intraoperative assessment of sentinel lymph node (SLN) status is critical for staging and guiding surgical management in gynaecological malignancies. Frozen-section histopathology remains the gold standard, but it is time-consuming and resource-intensive. Shear-wave elastography (SWE) quantifies tissue stiffness in real time and may offer a rapid alternative. Methods: In this prospective single-centre study, 63 women (median age 62 years) undergoing primary surgery with sentinel lymph node biopsy (SLNB) for endometrial, cervical, vulvar, or early ovarian carcinoma were enrolled. A total of 172 SLNs were excised, submerged in coupling gel, and scanned ex vivo using a 9 MHz linear probe. Results: A total of 172 SLNs underwent SWE (mean 2.7 nodes/patient). Endometrial primaries accounted for 58% of nodes, mostly retrieved by robotic-assisted surgery (71.8%). Node dimensions were significantly larger in malignant lesions for sonographic (long-axis: 13.02 ± 3.31 mm vs. 10.80 ± 3.28 mm; p = 0.002) and pathological long-axis measurements (11.45 ± 2.83 mm vs. 9.75 ± 2.61 mm; p = 0.004). Mean SWE velocities were similar between groups (1.381 ± 0.307 vs. 1.343 ± 0.236 m/s; p = 0.541). Histopathology identified metastases in 18% of SLNs, comprising macrometastases (7%), micrometastases (5%), and isolated tumour cells (6%). Conclusions: Although ex vivo SWE is rapid, reproducible, and integrates seamlessly into the sterile field, stiffness measurements alone lack sufficient discriminatory power for SLN staging in gynaecological cancers. Future research should focus on three-dimensional SWE, advanced radiomic analyses, and machine-learning algorithms to improve the detection of low-volume metastatic disease. Full article

Ovarian cancer continues to be the most lethal gynaecological malignancy, principally due to its late-stage diagnosis, extensive peritoneal dissemination, chemoresistance, and limitations of current imaging and therapeutic strategies. By optimising pharmacokinetics, refining tumour-selective drug delivery, and supporting high-resolution, multimodal imaging, nanomedicine offers a versatile platform to address these limitations. In this review, current progress across lipid-based, polymeric, inorganic, hybrid, and biomimetic nanocarriers is synthesised, emphasising how tailored physiochemical properties, surface functionalisation, and stimuli-responsive designs can improve tumour localisation, surmount stromal and ascetic barriers, and enable controlled drug release. Concurrently, significant advancement in imaging nanoprobes, including magnetic resonance imaging (MRI), positron emission tomography (PET)/single-photon emission computed tomography (SPECT), optical, near-infrared imaging (NIR), ultrasound, and photoacoustic systems, has evolved early lesion detection, intraoperative guidance, and quantitative monitoring of treatment. Diagnosis and therapy are further integrated within single platforms by emerging theranostic constructs, encouraging real-time visualisation of drug distribution and treatment response. Additionally, immune-nanomedicine, intraperitoneal depot systems, and nucleic acid-centred nanotherapies offer promising strategies to address immune suppression and molecular resistance in advanced ovarian cancer. In spite of noteworthy achievements, clinical translation is limited by complex manufacturing requirements, challenges with safety and stability, and restricted patient stratification. To unlock the full clinical potential of nanotechnology in ovarian cancer management, constant innovation in scalable design, regulatory standardisation, and integration of precision biomarkers will be necessary. Full article

Background/Objectives: Individuals carrying pathogenic/likely pathogenic (P/LP) variants associated with hereditary breast and ovarian cancer (HBOC) and Lynch Syndrome (LS)- have increased risk for various types of cancer. The study compared health behaviors, i.e., smoking, alcohol consumption, level of physical activity, and body mass index (BMI) among affected and unaffected (never diagnosed) individuals with P/LP variants associated with HBOC or LS. Methods: We used baseline and 18-month follow-up data from individuals with HBOC- or LS-associated P/LP variants from the Swiss CASCADE study, an open-ended, prospective, family-based cohort. Generalized linear models with random effects were applied. Results: A total of 856 records from 518 participants (HBOC: 410; LS: 108) were analyzed. More than half (58%) of participants had at least one cancer diagnosis. After controlling for potential confounders, the proportion of current smokers was not significantly different between the two groups (ß = 3.5, p = 0.24). Alcohol intake was not associated with cancer diagnosis (adjusted: ß = −0.2, p = 0.57), although it was positively associated with time since genetic testing (ß = 0.11, p < 0.01). Levels of physical activity were lower among affected individuals compared to unaffected (adjusted: ß = −0.5, p = 0.03). There was no difference in BMI between the two groups. Conclusions: No significant differences in health behaviors, i.e., smoking, alcohol consumption, or BMI, were detected in individuals with P/LP variants associated with HBOC or LS unaffected by cancer and those with cancer diagnosis. Lower levels of physical activity in those with a cancer diagnosis could potentially be attributed to cancer treatment. Future studies should examine whether adjustments in health behavior are associated with the genetic diagnosis. Full article

Background/Objectives: Pathogenic and likely pathogenic variants in the BRCA1 and BRCA2 genes are associated with a significantly increased risk of breast and/or ovarian cancer. We investigated genetic variants in a cohort of 450 unaffected individuals with a family history of breast and/or ovarian cancer, involving at least one first-degree relative. Methods: Next-generation sequencing (NGS) was used to analyze the coding regions of these two genes, with copy number variation (CNV) analysis. Results: A total of 16 unique to our cohort variants classified as pathogenic or likely pathogenic were identified in 22 patients, including one novel loss-of-function variant in BRCA1 gene. Furthermore, we identified a deletion of exon 21 in the BRCA1 gene in two patients. Conclusions: These results emphasize the difficulties involved in molecular diagnostics and indicate the need for further research into new predictive models for patients with hereditary breast and ovarian cancer. Full article

Background: Malignant ovarian tumours are most often detected at an advanced stage, when peritoneal dissemination across abdominal organs is already present. Metastasis in ovarian cancer arises from complex interactions between cancer cells and diverse components of the tumour microenvironment (TME), including extracellular matrix elements, fibroblasts, adipocytes, mesenchymal cells and leukocytes. This dynamic niche drives tumour progression, invasiveness and immunosuppression through cytokine- and chemokine-mediated signalling. A deeper understanding of these interactions may enable targeted modulation of the TME and help limit metastatic spread. Methods: In this study, using immunoenzymatic assays and a computational digital twin—a mechanistic, ODE-based in silico model that replicates key cellular and microenvironmental processes—we investigated whether and how caffeic acid phenethyl ester (CAPE) influences TME activation, cytokine and growth factor levels, and extracellular matrix remodelling. Results: Our findings show that CAPE modulates both pro- and antitumourigenic signalling pathways across immune, stromal and hypoxia-related axes, suggesting its potential to reshape the ovarian cancer microenvironment and improve therapeutic outcomes in this challenging malignancy. Conclusions: Taken together, these results indicate that CAPE may serve as a multifaceted modulator capable of simultaneously targeting tumour cells and their microenvironment, offering a promising avenue for enhancing therapeutic strategies in ovarian cancer. Full article

Background/Objectives: Epithelial ovarian cancer (EOC) encompasses ovarian, fallopian tube and peritoneal malignancies. It is a deadly disease and is rarely cured when diagnosed at advanced stages. Early-stage disease is often curable, but clinicians and researchers have been stymied in their attempts to reliably screen for this disease, even in high-risk populations. Effective prevention of ovarian cancer is usually limited to the use of combined oral contraceptives and removal of the ovaries and fallopian tubes. Methods and Results: We aim to review the current guidelines and the evidence reported for both the early detection and prevention of ovarian cancer. Novel imaging techniques, biomarkers, and surgical advances will be discussed. Conclusions: This review will offer (a) an understanding of the epidemiology of EOC (b) analysis and a discussion of relevant molecular markers that might be exploited for more accurate early detection (c) medical and surgical methods to prevent ovarian cancer. Full article

Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a hereditary cancer syndrome significantly increasing the risk of colorectal cancer (CRC) and various extracolonic cancers, including endometrial, ovarian, and gastric cancers. LS results from germline pathogenic variants (GPVs) in DNA mismatch repair (MMR) genes, such as MLH1, MSH2, MSH6, and PMS2, leading to microsatellite instability (MSI). This review explores the multifaceted aspects of LS, covering clinical presentation, genetic underpinnings, and emerging therapeutic strategies. The discussion explores the importance of identifying at-risk individuals, facilitating personalized cancer surveillance and prevention strategies. Molecular insights into distinguishing between sporadic and LS-associated cancers are also examined, with a focus on somatic testing methods, including MSI and immunohistochemistry (IHC). The gynecological cancer risks, particularly those related to endometrial and ovarian malignancies, are addressed, underscoring the need for early detection and risk-reducing interventions. Recent advancements in the management of colorectal and other LS-related cancers are highlighted, with particular attention to the growing role of immunotherapy, including immune checkpoint inhibitors, and immunoprevention strategies. With ongoing advances in our understanding of LS, opportunities for earlier detection, more effective prevention, and innovative treatments continue to expand. This narrative review adopts a multidisciplinary approach to provide a comprehensive understanding of LS, from its genetic basis to current clinical and therapeutic practices, with the ultimate goal of improving patient outcomes and enhancing the quality of care. Full article

Background: Ovarian cancer is characterized by high mortality rates, primarily due to diagnosis at late stages. Current biomarkers, such as CA125, have demonstrated limited efficacy for early detection. While high-dimensional proteomics offers a more comprehensive view of systemic biology, the analysis of such data, where the number of features far exceeds the number of samples, presents a significant computational challenge. Methods: This study utilized a nested case–control cohort of longitudinal pre-diagnostic serum samples from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) profiled for eight candidate ovarian cancer biomarkers (CA125, HE4, PEBP4, CHI3L1, FSTL1, AGR2, SLPI, DNAH17) and 92 additional cancer-associated proteins from the Olink Oncology II panel. We employed a Synolitic Graph Neural Network framework that transforms high-dimensional multi-protein data into sample-specific, interconnected graphs using a synolitic network approach. These graphs, which encode the relational patterns between proteins, were then used to train Graph Neural Network (GNN) models for classification. Performance of the network approach was evaluated together with conventional machine learning approaches via 5-fold cross-validation on samples collected within one year of diagnosis and a separate holdout set of samples collected one to two years prior to diagnosis. Results: In samples collected within one year of ovarian cancer diagnosis, conventional machine learning models—including XGBoost, random forests, and logistic regression—achieved the highest discriminative performance, with XGBoost reaching an ROC-AUC of 92%. Graph Convolutional Networks (GCNs) achieved moderate performance in this interval (ROC-AUC ~71%), with balanced sensitivity and specificity comparable to mid-performing conventional models. In the 1–2 year early-detection window, conventional model performance declined sharply (XGBoost ROC-AUC 46%), whereas the GCN maintained robust discriminative ability (ROC-AUC ~74%) with relatively balanced sensitivity and specificity. These findings indicate that while conventional approaches excel at detecting late pre-diagnostic signals, GNNs are more stable and effective at capturing subtle early molecular changes. Conclusions: The synolitic GNN framework demonstrates robust performance in early pre-diagnostic detection of ovarian cancer, maintaining accuracy where conventional methods decline. These results highlight the potential of network-informed machine learning to identify subtle proteomic patterns and pathway-level dysregulation prior to clinical diagnosis. This proof-of-concept study supports further development of GNN approaches for early ovarian cancer detection and warrants validation in larger, independent cohorts. Full article

Homologous recombination deficiency (HRD) is a clinically relevant biomarker that predicts sensitivity to PARP inhibitors and enables personalized cancer therapy. Validated local HRD testing solutions are essential to ensure timely and equitable access, ultimately improving treatment outcomes. We evaluated a shallow whole-genome sequencing (sWGS) approach for genomic instability (GI) assessment combined with a 52-gene targeted panel in ovarian cancer. Validation used reference materials and 24 archival samples with prior HRD characterization, comparing performance with the Myriad myChoice^® HRD test. A prospective cohort of 124 newly diagnosed ovarian cancer patients was then analyzed. sWGS-derived GI status showed strong concordance with the reference test (95.8% overall agreement; κ = 0.913; NPV 100%, PPV 93.3%). Pathogenic BRCA1/2 variants were detected in 30 patients (24.19%). An additional 22.76% were BRCA1/2-negative but GI-positive, giving an overall HRD prevalence of 47.15%. Platinum sensitivity occurred in 90.0% (18/20) of HRD-positive patients with follow-up. Among 12 patients assessed for PARP-inhibitor response, the overall response rate was 66.7% (95% CI 39.1–86.2) and disease control rate 83.3% (95% CI 55.2–95.3). TP53 alterations were most frequent (62.90%), followed by BRCA1 (19.35%) and BRCA2 (4.83%). Pathogenic variants in other HR-pathway genes (ATM, CHEK2, BRIP1, RAD51C, BARD1) appeared in 9.57% of BRCA-wild-type cases, with heterogeneous GI impact. Two cases showed concurrent BRCA2 variants and microsatellite instability, indicating possible eligibility for anti-PD-1/PD-L1 therapy in addition to PARPi. This first comprehensive analysis of Romanian ovarian cancer patients suggests that integrating sWGS-based genomic instability assessment with BRCA testing can improve HRD detection and reflects the heterogeneity of HR-pathway variants. Preliminary clinical observations were consistent with known HRD-associated treatment responses, although larger studies are needed to confirm these findings. Full article

Background: Hereditary breast and ovarian cancer is an inherited condition caused by pathogenic (P) or likely pathogenic (LP) variants in the BRCA1 and BRCA2 genes. Population-level sequencing allows for the identification of asymptomatic genotype-positive participants (GPPs) before disease onset. This study assessed the feasibility and impact of returning clinically relevant BRCA results to participants at the Qatar Precision Health Institute (QPHI). Methods: We established a structured framework to identify and refer asymptomatic individuals who were found to carry P/LP variants in BRCA among 6142 QPHI participants. The process integrated genomic analysis, participant recontact, counseling, referral, variants validation, and personalized risk-reducing strategies. Results: Six variants (four BRCA1, two BRCA2) were validated in ten GPPs with a median age of 48 years (IQR: 40.5–56). Eight variants were confirmed through Sanger sequencing in a CAP-accredited laboratory at Hamad Medical Corporation. All eligible participants were referred for counseling and personalized clinical management. Four men initiated breast and prostate cancer surveillance, while four women pursued breast and ovarian surveillance. One asymptomatic GPP underwent prophylactic salpingo-oophorectomy, revealing early-stage ovarian cancer. Cascade testing identified 20 additional GPPs and, in one asymptomatic relative, facilitated the detection of early-stage uterine cancer. The genetic testing acceptability rate was 0.77 (95% CI: 0.46–0.94), with a 100% adherence to surveillance at 12- and 24-month follow-ups. Conclusions: This pilot demonstrates the feasibility and clinical utility of returning actionable BRCA1/2 findings and represents the first initiative in an Arabic population to implement the return of medically actionable BRCA results from a population-based biobank. Full article

Background: Ovarian cancer ascites contributes to the immunosuppressive tumor microenvironment (TME) via macrophage-derived chemokine ligand 23 (CCL23) signaling, T-cell exhaustion, and upregulating pro-inflammatory cytokines. However, the extent to which ascites-derived CCL23 concentrations associate with changes in pro- and anti-inflammatory cytokines and overall patient survival in ovarian cancer patients remains unknown. Methods: CCL23 concentrations and pro-inflammatory cytokines were measured from ascites of stage III and IV epithelial ovarian cancer patients by ELISA and Luminex assays, respectively. Kaplan–Meier survival analysis was performed using patient outcome data from Stanford University Hospital and the Cancer Genome Atlas. The impact of CCL23 peptides on pro-inflammatory cytokine secretion was evaluated in vitro using differentiated THP-1 monocytes. Results: A total of 40 patients were enrolled and CCL23 concentrations were detected in all ascites samples (median = 2.42 ng/mL; range [0.06–6.45]). Reduced survival time corresponded with high CCL23 containing samples (mOS: 3.2 years, [3.9 ng/mL]) versus intermediate (mOS: 6.0 years, [2.5 ng/mL]) or low (mOS: 5.9 years; [1.4 ng/mL]) groups. TGCA analysis of patient outcomes was confirmatory. A significant negative correlation was observed between high CCL23 ascites concentrations versus CXCL10 and soluble PD-1 cytokine levels. High tumor expression of CXCL10 was associated with improved survival (mOS; 5.9 years) versus low CXCL10 expression (mOS; 3.2 years). In vitro, CCL23-stimulated THP-1 macrophages exhibited reduced CXCL10 secretion via STAT-3 activation. Conclusions: High CCL23 concentrations in ovarian cancer ascites reduces CXCL10 secretion from myeloid cells and associates with reduced patient survival. Full article

High-grade serous ovarian cancer (HGSOC) is the most commonly diagnosed ovarian cancer subtype. Approximately half of all patients diagnosed with HGSOC are deficient in homologous recombination (HR), harbor BRCA1/2 mutations, and are treated with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis). FDA-approved PARPis Olaparib, Niraparib, and Rucaparib all contribute to adverse effects in patients due to their poly-pharmacological properties. This feature necessitates investigation of global protein responses to PARPi treatment beyond DNA repair in the context of BRCA mutational status and HR deficiency. We sought to determine the landscape of differential PARPi-induced proteomes in HGSOC cells exhibiting different BRCA1/2 mutational statuses. Here, we applied immunofluorescence microscopy to detect γH2AX, Rad51, and geminin foci as markers of DNA damage and repair upon treatment of HGSOC cells with IC₅₀ doses of PARPis. Global proteome perturbations upon PARPi treatment were measured using quantitative mass spectrometry-based proteomics. The proteomic data highlighted cell line effects, masking high-dose PARPi treatment response. Interrogation of PARPi response within biological pathways identified through gene set enrichment analysis (GSEA) revealed significant changes to proteins involved in Epithelial–Mesenchymal Transition (EMT), E2F targets, and cholesterol homeostasis. Our study establishes proteomic evidence supporting the poly-pharmacological characteristics of Niraparib, Olaparib, and Rucaparib in HGSOC cells. Full article

Background/Objectives: Germline BRCA1 mutations account for ~15–20% of hereditary breast and ovarian cancer (HBOC) cases. While most are small sequence variants, structural rearrangements also contribute significantly to the pathogenic landscape. Conventional diagnostic workflows often miss such events, underscoring the need for comprehensive approaches. Here, we report a previously undescribed pathogenic mechanism—a transposon-mediated processed transcript insertion—expanding the mutational spectrum underlying hereditary breast cancer susceptibility. Methods: The studied case was discovered during our germline genotyping routine: next-generation sequencing followed by library preparation with a custom hereditary cancer panel. The identified variant was validated by orthogonal sequencing and multiplex ligation-dependent probe amplification (MLPA). RNA-level functional assays, including nonsense-mediated decay inhibition, were conducted to assess transcript stability. Constitutional origin was confirmed by analysis of multiple normal tissues, and tumor material was evaluated for loss of heterozygosity (LOH). Results: NGS detected a 700 bp insertion in exon 16 of BRCA1, corresponding to a complete processed transcript of RPL18A. The insertion caused a frameshift and premature stop codon, triggering degradation of the aberrant transcript. The variant was present in multiple somatic tissues, and its heritable nature was further confirmed by genotyping a first-degree relative, who was also found to carry the insertion. Tumor DNA analysis revealed strong LOH with retention of the variant allele. Conclusions: This study identifies, for the first time, a heritable processed transcript insertion as a pathogenic event in BRCA1. Such variants are undetectable by conventional diagnostic workflows lacking structural variant analysis, highlighting the importance of comprehensive approaches for accurate diagnosis and genetic counselling in hereditary cancer syndromes. Full article