miRNA-based electrochemical biosensors for ovarian cancer.

Ovarian cancer, a prevalent and deadly cancer among women, presents a significant challenge for early detection due to its heterogeneous nature. MicroRNAs, short non-coding regulatory RNA fragments, play a role in various cellular processes. Aberrant expression of these microRNAs has been observed in the carcinogenesis-related processes of many cancer types. Numerous studies highlight the critical role of microRNAs in the initiation and progression of ovarian cancer. Given their clinical importance and predictive value, there has been considerable interest in developing simple, prompt, and sensitive miRNA biosensor strategies. Among these, electrochemical sensors have demonstrated advantageous characteristics such as simplicity, sensitivity, low cost, and scalability. These microRNA-based electrochemical biosensors are valuable tools for early detection and point-of-care applications. This article discusses the potential role of microRNAs in ovarian cancer and recent advances in the development of electrochemical biosensors for miRNA detection in ovarian cancer samples.

Hyperplastic ovarian stromal cells express genes associated to tumor progression: a case study.

The current study presents the analysis of stromal cells obtained from an hyperplastic left-ovary of a Holstein cow. Cultured hyperplastic stromal cells displayed a fibroblast-like morphology and ceased proliferation after the 8th passage. The non-cancerous nature of stromal cells was confirmed by in vitro cell proliferation and migration assays. Negligible amounts of E2 were detected in the spent media of cultured stromal cells, which suggests that stromal cells were non-estradiol synthesizing cells. As revealed in immunofluorescence and gene expression analysis, the hyperplastic stromal cells explicitly expressed vimentin in their cytoskeleton. Upon hematoxylin staining, a highly dense population of stromal cells was observed in the stromal tissue of the hyperplastic ovary. To explore genome-wide alterations, mRNA microarray analysis was performed using Affymetrix Bovine Gene 1.0ST Arrays compared to normal ovarian derived stromal cells. The microarray identified 1396 differentially expressed genes, of which 733 were up- and 663 down-regulated in hyperplastic stromal cells. Importantly, asporin (ASPN) and vascular cell adhesion molecule 1 (VCAM1) were among the highly up-regulated genes. Higher expression of ASPN was also confirmed by immunohistochemistry and RT-qPCR analysis. Ingenuity pathway analysis (IPA) identified about 98 significantly enriched (-log (p value ≥ 1.3) canonical pathways, importantly of which the "Sirutin Signaling Pathway" and "Mitochondrial Dysfunction" were highly activated while "Oxidative phosphorylation" was inhibited. Additionally, higher proportion of hyperplastic stromal cells in the S-phase of cell cycle, could be attributed to higher expression levels of cell proliferation genes such as CCND2 and CDK6.

The application value of two-dimensional ultrasound combined with contrast-enhanced ultrasound in the differential diagnosis of benign, borderline, and malignant ovarian epithelial tumors.

OBJECTIVE: The aim of this study was to explore the clinical application value of two-dimensional ultrasound (2D-US) combined with contrast-enhanced ultrasonography (CEUS) in the differential diagnosis of benign, borderline ovarian tumors (BOTs), and malignant ovarian epithelial tumors (OETs). METHODS: The clinical data of 108 patients who underwent surgery for pathologically confirmed of OETs at Peking University People's Hospital between December 2018 and November 2023 were retrospectively studied. The diagnostic value of 2D-US combined with CEUS for diagnosing OETs was analyzed using chi-square tests, receiver operating characteristic (ROC) curves, and random forest models. RESULTS: Among the 108 cases of OETs, 23 were benign, 34 were BOTs, and 51 were malignant. Chi-square tests confirmed that the perfusion pattern of the contrast agent plays an important role in the differential diagnosis of OETs. Compared with those in the benign group, the BOTs were not significantly different in terms of perfusion phase and enhancement intensity, but the regression time of the BOTs was earlier (P < 0.05). Compared with the BOTs, the malignant tumors group showed earlier perfusion and higher enhancement intensity, with no significant difference in regression time. The ROC curve results indicated that the combined diagnostic efficiency of 2D-US and CEUS in distinguishing OETs was significantly higher than that of a single diagnostic technique in terms of sensitivity, specificity, accuracy, and AUC. The random forest model results revealed that among the various parameters used in the differential diagnosis of OETs, the perfusion pattern was the most significant factor. CONCLUSION: 2D-US combined with CEUS helps improve the differential diagnostic efficiency for benign, BOTs, and malignant OETs.

Neoadjuvant chemotherapy induces phenotypic mast cell changes in high grade serous ovarian cancer.

BACKGROUND: High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy in which patients have still yet to respond meaningfully to clinically available immunotherapies. Hence, novel immune targets are urgently needed. Our past work has identified that mast cells are significantly upregulated at the mRNA level in HGSOC patient tumors following neoadjuvant chemotherapy (NACT) exposure. Therefore, in this current investigation we sought to characterize intratumoral mast cell phenotypic changes as a result of NACT exposure and determine how these adaptations are associated with patient clinical outcomes. METHODS: Hematologic immunohistochemistry was employed to determine mast cell levels in 36 matched pre- and post-NACT HGSOC patient tumors. Fluorescent Immunohistochemistry was utilized to identify Tryptase+(carboxypeptidase A3 (CPA3) + mast cells as well as histamine levels in 29 and 20, respectively, matched pre- and post-NACT HGSOC patient tumors. Finally, human immortalized mast cells, LUVA were stimulated with carboplatin and paclitaxel and genomic changes were analyzed by quantitative PCR. RESULTS: Hematologic labeled intratumoral mast cells were significantly upregulated in the intraepithelial and stromal regions of the tumor, post-NACT. Lower levels of pre-NACT mast cells were significantly associated with an improved progression-free survival (PFS). Histamine, a marker of mast cell degranulation was similarly upregulated in post-NACT exposed tumors. Through the characterization of mast cell specific proteases Tryptase and CPA3, it was found that Tryptase+/ CPA3 + mast cells were significantly upregulated both in the intraepithelial and stromal compartments of the tumor, while Tryptase + cells were significantly upregulated in the stromal regions of the tumor. Lower post-NACT treated levels with Tryptase+/ CPA3 + cells were significantly associated with improved overall survival (OS) and PFS while higher Tryptase + mast cells were associated with improved OS. Finally, following chemotherapy exposure mast cell activating factors AREG and CCL2 were significantly upregulated while TGFB1, an inhibitor of mast cell activation was downregulated in LUVA cells. CONCLUSIONS: Enhanced mast cell numbers, as well as activation and degranulation are a consequence of NACT exposure. Post-NACT mast cells displayed differing associations with survival outcomes that was dependent upon granule classification. Ultimately, mast cells represent a clinically relevant putative HGSOC immune target.

Novel protein-based prognostic signature linked to immunotherapeutic efficiency in ovarian cancer.

BACKGROUND: Personalized medicine remains an unmet need in ovarian cancer due to its heterogeneous nature and complex immune microenvironments, which has gained increasing attention in the era of immunotherapy. A key obstacle is the lack of reliable biomarkers to identify patients who would benefit significantly from the therapy. While conventional clinicopathological factors have exhibited limited efficacy as prognostic indicators in ovarian cancer, multi-omics profiling presents a promising avenue for comprehending the interplay between the tumor and immune components. Here we aimed to leverage the individual proteomic and transcriptomic profiles of ovarian cancer patients to develop an effective protein-based signature capable of prognostication and distinguishing responses to immunotherapy. METHODS: The workflow was demonstrated based on the Reverse Phase Protein Array (RPPA) and RNA-sequencing profiles of ovarian cancer patients from The Cancer Genome Atlas (TCGA). The algorithm began by clustering patients using immune-related gene sets, which allowed us to identify immune-related proteins of interest. Next, a multi-stage process involving LASSO and Cox regression was employed to distill a prognostic signature encompassing five immune-related proteins. Based on the signature, we subsequently calculated the risk score for each patient and evaluated its prognostic performance by comparing this model with conventional clinicopathological characteristics. RESULTS: We developed and validated a protein-based prognostic signature in a cohort of 377 ovarian cancer patients. The risk signature outperformed conventional clinicopathological factors, such as age, grade, stage, microsatellite instability (MSI), and homologous recombination deficiency (HRD) status, in terms of prognoses. Patients in the high-risk group had significantly unfavorable overall survival (p < 0.001). Moreover, our signature effectively stratified patients into subgroups with distinct immune landscapes. The high-risk group exhibited higher levels of CD8 T-cell infiltration and a potentially greater proportion of immunotherapy responders. The co-activation of the TGF-ß pathway and cancer-associated fibroblasts could impair the ability of cytotoxic T cells to eliminate cancer cells, leading to poor outcomes in the high-risk group. CONCLUSIONS: The protein-based signature not only aids in evaluating the prognosis but also provides valuable insights into the tumor immune microenvironments in ovarian cancer. Together our findings highlight the importance of a thorough understanding of the immunosuppressive tumor microenvironment in ovarian cancer to guide the development of more effective immunotherapies.

Niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer: final results of a multicenter phase 2 study.

OBJECTIVE: To evaluate the long-term efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer. METHODS: This was the follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with homologous recombination-deficient, platinum-sensitive, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of chemotherapy and were poly(ADP-ribose) polymerase inhibitor naïve. Participants received niraparib (starting dose, 300 mg) once daily in continuous 28-day cycles until objective disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was confirmed objective response rate (ORR), as assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Safety evaluations included treatment-emergent adverse events (TEAEs). RESULTS: 20 patients were enrolled in the study and included in both efficacy and safety analyses. Median total study duration was 759.5 days. Median dose intensity was 201.3 mg/day. Confirmed ORR was 60.0% (90% confidence interval [CI]=39.4-78.3); 2 patients had complete response and 10 patients had partial response. Median duration of response was 9.9 months (95% CI=3.9-26.9) and the disease control rate was 90.0% (95% CI=68.3-98.8). The most common TEAEs were anemia (n=15), nausea (n=12), and decreased platelet count (n=11). TEAEs leading to study drug dose reduction, interruption, or discontinuation were reported in 16 (80.0%), 15 (75.0%), and 2 patients (10.0%), respectively. CONCLUSION: The long-term efficacy and safety profile of niraparib was consistent with previous findings in the equivalent population in non-Japanese patients. No new safety signals were identified. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759600.

Human papillomavirus infection of the fallopian tube as a potential risk factor for epithelial ovarian cancer.

Human papillomaviruses (HPVs) and herpesviruses are detected in patients with epithelial ovarian cancer (EOC). We sought to analyze the prevalence of HPV's 16 and 18, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) DNA in peripheral blood, ovarian, and fallopian tube (FT) tissue samples collected from 97 EOC patients, including 71 cases of high-grade serous ovarian carcinoma (HGSOC), and from 60 women with other tumors or non-neoplastic gynecological diseases. DNA isolates were analyzed by PCR methods, including droplet digital PCR. The results demonstrate that (1) HPV16 DNA has been detected in one-third of the FT and tumor samples from EOCs; (2) the prevalence and quantity of HPV16 DNA were significantly higher in FT samples from HGSOCs, non-HGSOCs, and ovarian metastases than in those from non-neoplastic diseases; (3) CMV and EBV have been detected in approximately one-seventh of EOC samples. The results suggest that HPV16 might be a potential risk factor for EOC development.

Profiling of metabolic dysregulation in ovarian cancer tissues and biofluids.

Ovarian cancer (OC) is the most lethal gynecologic cancer, mainly due to late diagnosis with widespread peritoneal spread at first presentation. We performed metabolomic analyses of ovarian and paired control tissues using capillary electrophoresis-mass spectrometry and liquid chromatography-mass spectrometry to understand its metabolomic dysregulation. Of the 130 quantified metabolites, 96 metabolites of glycometabolism, including glycolysis, tricarboxylic acid cycles, urea cycles, and one-carbon metabolites, showed significant differences between the samples. To evaluate the local and systemic metabolomic differences in OC, we also analyzed low or non-invasively available biofluids, including plasma, urine, and saliva collected from patients with OC and benign gynecological diseases. All biofluids and tissue samples showed consistently elevated concentrations of N1,N12-diacetylspermine compared to controls. Four metabolites, polyamines, and betaine, were significantly and consistently elevated in both plasma and tissue samples. These data indicate that plasma metabolic dysregulation, which the most reflected by those of OC tissues. Our metabolomic profiles contribute to our understanding of metabolomic abnormalities in OC and their effects on biofluids.

Adipocyte derived exosomes promote cell invasion and challenge paclitaxel efficacy in ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is the deadliest gynaecological cancer with high mortality rates driven by the common development of resistance to chemotherapy. EOC frequently invades the omentum, an adipocyte-rich organ of the peritoneum and omental adipocytes have been implicated in promoting disease progression, metastasis and chemoresistance. The signalling mechanisms underpinning EOC omentum tropism have yet to be elucidated. METHODS: Three-dimensional co-culture models were used to explore adipocyte-EOC interactions. The impact of adipocytes on EOC proliferation, response to therapy and invasive capacity was assessed. Primary adipocytes and omental tissue were isolated from patients with ovarian malignancies and benign ovarian neoplasms. Exosomes were isolated from omentum tissue conditioned media and the effect of omentum-derived exosomes on EOC evaluated. Exosomal microRNA (miRNA) sequencing was used to identify miRNAs abundant in omental exosomes and EOC cells were transfected with highly abundant miRNAs miR-21, let-7b, miR-16 and miR-92a. RESULTS: We demonstrate the capacity of adipocytes to induce an invasive phenotype in EOC populations through driving epithelial-to-mesenchymal transition (EMT). Exosomes secreted by omental tissue of ovarian cancer patients, as well as patients without malignancies, induced proliferation, upregulated EMT markers and reduced response to paclitaxel therapy in EOC cell lines and HGSOC patient samples. Analysis of the omentum-derived exosomes from cancer patients revealed highly abundant miRNAs that included miR-21, let-7b, miR-16 and miR-92a that promoted cancer cell proliferation and protection from chemotherapy when transfected in ovarian cancer cells. CONCLUSIONS: These observations highlight the capacity of omental adipocytes to generate a pro-tumorigenic and chemoprotective microenvironment in ovarian cancer and other adipose-related malignancies.

Diagnosis of a large cystic teratoma of accessory ovary complicated with torsion by ultrasound: A case report.

RATIONALE: An accessory ovary complicated by cystic teratoma and torsion is extremely rare and requires prompt diagnosis and surgical treatment. However, evidence for effective preoperative imaging diagnosis has barely been reported. Our study presented a case in which preoperative ultrasound reasonably suspected ovarian tumor torsion and an accessory ovary, and laparoscopic surgery was strategically performed. PATIENT CONCERNS: An 18-year-old girl had persistent pain in the lower right abdomen for over 7 hours accompanied by nausea and vomiting, and she had a 14.1 × 10.1 × 9.0 cm hypo-echoic cystic lesion containing a 6.4 × 4.9 × 3.0 cm solid component accompanied by the whirlpool sign on the right side of the pelvis. Additionally, a hyper-echoic ovary with a size of 2.5 × 1.4 cm and a normal ovary appearance of 2.4 × 0.8 cm were detected on the right side of the adnexal area by ultrasound. DIAGNOSIS: The cystic lesion was a large accessory ovarian cystic teratoma, complicated by torsion. The hyperechoic ovary appears as accessory ovarian stromal edema and the normal ovary appearance is eutopic. INTERVENTIONS: Single-port laparoscopic resection of the ovarian lesion, release of the ovarian torsion, and oophoroplasty were performed. OUTCOMES: Postoperative recovery was unremarkable. Antral follicles were detected in both eutopic and accessory ovaries by ultrasound 20 days and 4 months after surgery. In addition, during the second postoperative ultrasound follow-up, the accessory ovary showed no difference in echo compared to the normal ovary, except for a slightly larger volume. LESSONS: Clinical manifestations of accessory ovarian tumors combined with torsion are similar to those of eutopic ovarian torsion, and timely surgery is required.

Effectiveness of the Traditional Japanese Medicine Goshajinkigan in Preventing Paclitaxel-Induced Peripheral Neuropathy: A Multicenter Randomized Comparative Trial.

Objective: Development of chemotherapy-induced peripheral neuropathy (CIPN) poses significant challenges in cancer treatment, often leading to dose reductions or treatment discontinuation. Goshajinkigan (GJG), a traditional Japanese medicine, has shown promise for alleviating CIPN symptoms. This multicenter, randomized controlled trial aimed to prospectively examine the efficacy of GJG in preventing paclitaxel-induced peripheral neuropathy. Methods: This study enrolled 55 patients with ovarian cancer undergoing first-line chemotherapy using paclitaxel and carboplatin. The participants were randomized into Groups A (GJG initiation after onset of grade 2 neuropathy) and B (prophylactic administration of GJG from 1 week before chemotherapy). The primary endpoints were the proportion with a maximum sensory neuropathy grade and visual analog scale (VAS) scores. The secondary endpoints were the rate of chemotherapy completion and paclitaxel dose reduction due to neurotoxicity. Results: Prophylactic GJG administration (Group B) resulted in significant benefits. While both groups had a similar incidence of grade 2 sensory neuropathy, all patients in Group B with grade 2 neuropathy completed treatment without requiring additional analgesics. Group B exhibited lower VAS scores by the end of the study, reduced reliance on adjuvant analgesics (27.3% vs 66.7% in Group A), and significantly less frequent persistent CIPN 6 months post-chemotherapy (18.2% vs 55.6% in Group A). No differences were observed in the chemotherapy completion rates or CIPN-related changes between the groups. Conclusion: GJG, when administered prophylactically, showed potential for mitigating CIPN symptoms during paclitaxel chemotherapy. While promising, further research with placebo controls and objective measures is essential to comprehensively validate these findings.

High-throughput drug screening identifies novel therapeutics for Low Grade Serous Ovarian Carcinoma.

Low grade serous carcinoma (LGSOC) is a rare epithelial ovarian cancer with unique molecular characteristics compared to the more common tubo-ovarian high-grade serous ovarian carcinoma. Pivotal clinical trials guiding the management of epithelial ovarian cancer lack sufficient cases of LGSOC for meaningful subgroup analysis, hence overall findings cannot be extrapolated to rarer chemo-resistant subtypes such as LGSOC. Furthermore, there is a need for more effective therapies for the treatment of relapsed disease, as treatment options are limited. To address this, we conducted the largest quantitative high-throughput drug screening effort (n = 3436 compounds) in 12 patient-derived LGSOC cell lines and one normal ovary cell line to identify unexplored therapeutic avenues. Using a combination of high-throughput robotics, high-content imaging and novel data analysis pipelines, our data set identified 60 high and 19 moderate confidence hits which induced cancer cell specific cytotoxicity at the lowest compound dose assessed (0.1 µM). We also revealed a series of known (mTOR/PI3K/AKT) and novel (EGFR and MDM2-p53) drug classes in which LGSOC cell lines showed demonstrable susceptibility to.

Management strategy of primary ovarian mucinous carcinoid tumor: A rare case report.

RATIONALE: Primary ovarian carcinoid tumors are rare neoplasms, first reported in 1939, with approximately 30 cases reported thus far. It is categorized into insular, trabecular, strumal, and mucinous types. Mucinous forms are extremely rare, comprising < 2% of all primary ovarian carcinoid tumors. PATIENT CONCERNS: A 40-year-old gravida 3, para 0 woman visited our clinic with a 3-month history of lower abdominal pain. Ultrasound and abdominal pelvic computed tomography revealed a large, poorly enhancing soft tissue mass in the right adnexa (about 9.4 × 7.0 × 6.8 cm sized). Laparoscopic surgery was performed to a definitive diagnosis, including right salpingo-oophorectomy, left ovarian biopsy, and ascites washing cytology. DIAGNOSIS: The patient was diagnosed with primary ovarian mucinous carcinoid tumor and received related treatment. OUTCOMES: After treatment, the patient symptoms improved, and he was discharged. LESSONS: Approximately 40% of primary ovarian carcinoid tumors with insular morphology present in pure form, and mucinous forms are extremely rare. At present, the main diagnostic methods in cases of primary ovarian mucinous carcinoid tumor include macroscopic examination, histopathology and imaging examination. The main treatment modalities for primary ovarian mucinous carcinoid tumor are surgery. postoperative chemotherapy remains controversial.

Safe to save blood in ovarian cancer surgery - time to change transfusion habits.

BACKGROUND: Patients with advanced ovarian cancer (AOC) undergoing surgery are often subjected to red blood cell (RBC) transfusions. Both anemia and RBC transfusion are associated with increased morbidity. The aim was to evaluate patient recovery after the implementation of patient blood management (PBM) strategies. METHODS: This retrospective cohort study included 354 patients with AOC undergoing surgery at Skane University Hospital Lund, Sweden, between January 2016 and December 2021. The gradual implementation of PBM strategies included restrictive RBC transfusion, tranexamic acid as standard medication before laparotomies and intravenous iron administered to patients with iron deficiency. Severe complications were defined as Clavien-Dindo (CD) grade ≥ 3a. Logistic and linear regression analyses were used to evaluate the differences between three consecutive periods. RESULTS: After the implementation of new strategies, 52% of the patients had at least one transfusion compared to 83% at baseline (p < 0.001). There was no difference in the rate of severe complications (CD ≥ 3a) between the groups, adjusted odds ratio 0.55 (95% CI 0.26-1.17). The mean difference in hemoglobin before chemotherapy was -1.32 g/L (95% CI -3.04 to -0.22) when adjusted for blood loss and days from surgery to chemotherapy. The length of stay (LOS) decreased from 8.5 days to 7.5 days (p 0.002). INTERPRETATION: The number of patients transfused were reduced by 31%. Despite a slight increase in anemia rate, severe complications (CD ≥ 3a) remained stable. The LOS was reduced, and chemotherapy was given without delay, indicating that PBM is feasible and without causing major severe effects on short-term recovery.

The association between oral contraceptive pills and ovarian cancer risk: A systematic review and meta-analysis.

INTRODUCTION: Previous study results have been inconclusive, so this meta-analysis aims to evaluate the association between ovarian cancer and oral contraceptive pills (OCPs). METHODS: PubMed, EMBASE, Scopus, and Web of Science were searched to identify studies on the association between OCPs and ovarian cancer from January 1, 2000 through February 5, 2023. The pooled relative risk (RR) and odds ratio (OR) were used to measure this relationship. RESULTS: A total of 67 studies were included. In the association between ever-use compared with never-use of OCPs and ovarian cancer risk, the pooled RR in cohort studies was 0.69 [95% CI: 0.61, 0.78]. For the relationship between duration of OCPs use and ovarian cancer in the cohort studies, no association between duration of use1-12 months 0.92 [95% CI: 0.82, 1.03] and duration of use 13-60 months 0.87 [95% CI: 0.73, 1.04], but there is a statistically significant inverse relationship between duration of use 61-120 months 0.62 [95% CI: 0.48, 0.81] and more than 120 months 0.51 [95% CI: 0.32, 0.80] and ovarian cancer. For the relationship between OCPs and histological subtype of epithelial ovarian cancer in the cohort studies, the pooled RR for invasive was 0.70 [95% CI: 0.56, 0.87], but no association between OCPs and borderline ovarian cancer 0.64 [95% CI: 0.31, 1.31]. CONCLUSION: Our analysis shows a statistically significant inverse relationship between ever-use compared to never-use of OCPs and ovarian cancer risk,and also between invasive cancer and OCPs. By increasing the duration of OCPs use, the risk of ovarian cancer decreased.

MYC is Sufficient to Generate Mid-Life High-Grade Serous Ovarian and Uterine Serous Carcinomas in a p53-R270H Mouse Model.

Genetically engineered mouse models (GEMM) have fundamentally changed how ovarian cancer etiology, early detection, and treatment are understood. MYC, an oncogene, is amongst the most amplified genes in high-grade serous ovarian cancer (HGSOC), but it has not previously been utilized to drive HGSOC GEMMs. We coupled Myc and dominant-negative mutant p53-R270H with a fallopian tube epithelium (FTE)-specific promoter Ovgp1 to generate a new GEMM of HGSOC. Female mice developed lethal cancer at an average of 14.5 months. Histopathologic examination of mice revealed HGSOC characteristics, including nuclear p53 and nuclear MYC in clusters of cells within the FTE and ovarian surface epithelium. Unexpectedly, nuclear p53 and MYC clustered cell expression was also identified in the uterine luminal epithelium, possibly from intraepithelial metastasis from the FTE. Extracted tumor cells exhibited strong loss of heterozygosity at the p53 locus, leaving the mutant allele. Copy-number alterations in these cancer cells were prevalent, disrupting a large fraction of genes. Transcriptome profiles most closely matched human HGSOC and serous endometrial cancer. Taken together, these results demonstrate that the Myc and Trp53-R270H transgenes were able to recapitulate many phenotypic hallmarks of HGSOC through the utilization of strictly human-mimetic genetic hallmarks of HGSOC. This new mouse model enables further exploration of ovarian cancer pathogenesis, particularly in the 50% of HGSOC which lack homology-directed repair mutations. Histologic and transcriptomic findings are consistent with the hypothesis that uterine serous cancer may originate from the FTE. SIGNIFICANCE: Mouse models using transgenes which generate spontaneous cancers are essential tools to examine the etiology of human diseases. Here, the first Myc-driven spontaneous model is described as a valid HGSOC model. Surprisingly, aspects of uterine serous carcinoma were also observed in this model.

Targeting GPX4-mediated ferroptosis protection sensitizes BRCA1-deficient cancer cells to PARP inhibitors.

BRCA1 is one of the most frequently-mutated tumor suppressor genes in ovarian and breast cancers. Loss of BRCA1 triggers homologous recombination (HR) repair deficiency, consequently leading to genomic instability and PARP inhibitors (PARPi)-associated synthetic lethality. Although, the roles of BRCA1 in DNA repair and replication have been extensively investigated, its tumor suppressive functions beyond genome safeguard remain poorly understood. Here, we report that BRCA1 promotes ferroptosis susceptibility through catalyzing K6-linked polyubiquitination of GPX4 and subsequently accelerating GPX4 degradation. Depletion of BRCA1 induces ferroptosis resistance in ovarian cancer cells due to elevated GPX4 protein, and silence of GPX4 significantly suppresses the growth of BRCA1-deficient ovarian cancer xenografts. Importantly, we found that PARPi triggers ferroptosis in ovarian cancer cells, inhibition of GPX4 markedly increase PARPi-induced ferroptosis in BRCA1-deficient ovarian cancer cells. Combined treatment of GPX4 inhibitor and PARPi produces synergistic anti-tumor efficacy in BRCA1-deficient ovarian cancer cells, patient derived organoid (PDO) and xenografts. Thus, our study uncovers a novel mechanism via which BRCA1 exerts tumor suppressive function through regulating ferroptosis, and demonstrates the potential of GPX4 as a therapeutic target for BRCA1-mutant cancers.

Screening Familial Risk for Hereditary Breast and Ovarian Cancer.

Importance: Most patients with pathogenic or likely pathogenic (P/LP) variants for breast cancer have not undergone genetic testing. Objective: To identify patients meeting family history criteria for genetic testing in the electronic health record (EHR). Design, Setting, and Participants: This study included both cross-sectional (observation date, February 1, 2024) and retrospective cohort (observation period, January 1, 2018, to February 1, 2024) analyses. Participants included patients aged 18 to 79 years enrolled in Renown Health, a large health system in Northern Nevada. Genotype was known for 38 003 patients enrolled in Healthy Nevada Project (HNP), a population genomics study. Exposure: An EHR indicating that a patient is positive for criteria according to the Seven-Question Family History Questionnaire (hereafter, FHS7 positive) assessing familial risk for hereditary breast and ovarian cancer (HBOC). Main Outcomes and Measures: The primary outcomes were the presence of P/LP variants in the ATM, BRCA1, BRCA2, CHEK2, or PALB2 genes (cross-sectional analysis) or a diagnosis of cancer (cohort analysis). Age-adjusted cancer incidence rates per 100 000 patients per year were calculated using the 2020 US population as the standard. Hazard ratios (HRs) for cancer attributable to FHS7-positive status were estimated using cause-specific hazard models. Results: Among 835 727 patients, 423 393 (50.7%) were female and 29 913 (3.6%) were FHS7 positive. Among those who were FHS7 positive, 24 535 (82.0%) had no evidence of prior genetic testing for HBOC in their EHR. Being FHS7 positive was associated with increased prevalence of P/LP variants in BRCA1/BRCA2 (odds ratio [OR], 3.34; 95% CI, 2.48-4.47), CHEK2 (OR, 1.62; 95% CI, 1.05-2.43), and PALB2 (OR, 2.84; 95% CI, 1.23-6.16) among HNP female individuals, and in BRCA1/BRCA2 (OR, 3.35; 95% CI, 1.93-5.56) among HNP male individuals. Being FHS7 positive was also associated with significantly increased risk of cancer among 131 622 non-HNP female individuals (HR, 1.44; 95% CI, 1.22-1.70) but not among 114 982 non-HNP male individuals (HR, 1.11; 95% CI, 0.87-1.42). Among 1527 HNP survey respondents, 352 of 383 EHR-FHS7 positive patients (91.9%) were survey-FHS7 positive, but only 352 of 883 survey-FHS7 positive patients (39.9%) were EHR-FHS7 positive. Of the 29 913 FHS7-positive patients, 19 764 (66.1%) were identified only after parsing free-text family history comments. Socioeconomic differences were also observed between EHR-FHS7-negative and EHR-FHS7-positive patients, suggesting disparities in recording family history. Conclusions and Relevance: In this cross-sectional study, EHR-derived FHS7 identified thousands of patients with familial risk for breast cancer, indicating a substantial gap in genetic testing. However, limitations in EHR family history data suggested that other identification methods, such as direct-to-patient questionnaires, are required to fully address this gap.

Ovarian Cancer Patient-Derived Organoids Used as a Model for Replicating Genetic Characteristics and Testing Drug Responsiveness: A Preliminary Study.

This study aimed to explore the role of ovarian cancer patient-derived organoids (PDOs) in their replicating genetic characteristics and testing drug responsiveness. Ovarian cancer PDOs were cultured in Matrigel with a specialized medium. The successful rate and proliferation rate were calculated. Morphology, histology, and immunohistochemistry (IHC) (PAX8, P53, and WT1) were used to identify the tumor characteristics. Gene sequencing, variant allele frequency (VAF), and copy number variation were used to explore the mutation profile. The sensitivity to chemodrugs (carboplatin, paclitaxel, gemcitabine, doxorubicin, and olaparib) was conducted. Successful generation of organoids occurred in 54% (7/13) of attempts, encompassing 4 high-grade serous carcinomas (HGSC), 1 mucinous carcinoma (MC), 1 clear cell carcinoma (CCC), and 1 carcinosarcoma. The experiments used six organoids (3 HGSC, 1 CCC, 1 MC, and 1 carcinosarcoma). The derived organoids exhibited spherical-like morphology, and the diameter ranged from 100 to 500 µm. The histology and IHC exhibited the same between organoids and primary tumors. After cryopreservation, the organoid's growth rate was slower than the primary culture (14 days vs 10 days, P < 0.01). Targeted sequencing revealed shared DNA variants, including mutations in key genes, such as BRCA1, PIK3CA, ARID1A, and TP53. VAF was similar between primary tumors and organoids. The organoids maintained inherited most copy number alterations. Drug sensitivity testing revealed varying responses, with carcinosarcoma organoids showing higher sensitivity to paclitaxel and gemcitabine than HGSC organoids. Our preliminary results showed that ovarian cancer PDOs could be successfully derived and histology, mutations, and diverse copy numbers of genotypes could be faithfully captured. Drug testing could reveal the individual PDO's responsiveness to drugs. PDOs might be as valuable resources for investigating genomic biomarkers for personalized treatment.