Wei Liu

Genetic Causal Relationship Between Systemic Lupus Erythematosus and Malignant Tumors of the Female Reproductive System: A GWAS Analysis in European Populations

Background: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that primarily affects women of reproductive age. Existing studies have demonstrated complex associations between SLE and various diseases, but its genetic relationship with malignant tumors of the female reproductive system has not been fully elucidated. This study is aimed at exploring the potential genetic associations and shared molecular basis between SLE and female reproductive system malignancies using genome‐wide association studies (GWASs) and cross‐trait analysis.Methods: We selected genetic variants significantly associated with SLE (p < 5 × 10−8) from large‐scale GWAS databases as genetic instruments and applied various statistical methods to analyze the associations between SLE and cervical cancer, endometrial cancer, ovarian cancer, vulvar cancer, vaginal cancer, and uterine cancer. The primary analysis was conducted using inverse variance weighting (IVW), supplemented by Egger regression, weighted median, and weighted mode methods. To control for potential confounders, we performed multivariable analysis while including BMI, estradiol, and CRP as covariates. Additionally, cross‐trait analysis using the association analysis based on subset (ASSET) method was employed to identify shared genetic variants and their effect directions between SLE and uterine cancer.Results: Genetic association analysis showed a significant negative association between SLE and endometrial cancer (OR = 0.972, 95% CI [0.946–0.998], p = 0.038), suggesting that SLE may be associated with a reduced risk of endometrial cancer. For uterine cancer, the weighted median method also indicated a marginally significant negative association (OR = 0.955, 95% CI [0.912–1.000], p = 0.049). Multivariable analysis further confirmed that the protective association between SLE and endometrial cancer remained significant after controlling for BMI, estradiol, and CRP (OR = 0.96, 95% CI [0.93–0.99], p = 0.014). However, no significant association was observed between SLE and cervical cancer, ovarian cancer, vulvar cancer, or vaginal cancer. Cross‐trait analysis identified 193 shared genetic variants between SLE and endometrial cancer and 71 shared variants between SLE and uterine cancer, with rs2442719 and rs3131004 showing consistent effect directions in both comparisons.Conclusion: This study provides genetic epidemiological evidence suggesting that SLE may have a protective effect against endometrial and uterine cancers and identifies potential shared genetic bases. These findings offer new insights into the relationship between SLE and gynecological tumors and may provide references for the prevention and treatment of related diseases.

Fertility-preserving treatment outcome in endometrial cancer or atypical hyperplasia patients with polycystic ovary syndrome

This study aimed to investigate the impact of polycystic ovary syndrome (PCOS) on fertility-sparing treatment in young patients with atypical endometrial hyperplasia (AEH) or endometrioid endometrial cancer (EEC). A total of 285 patients with EEC (n=76, FIGO stage IA, without myometrium invasion) or AEH (n=209) who received progestin-based fertility-sparing treatment were evaluated retrospectively. Among the 285 patients, 103 (36.1%), including 70 AEH cases and 33 EEC cases, were diagnosed with PCOS. General characteristics, cumulative 16- and 32-week complete response (CR) rate, pregnancy outcome and recurrence were compared between patients with or without PCOS. The cumulative 16-week CR rate was lower in the PCOS group than in the non-PCOS group (18.4% vs. 33.8%, p=0.006). Patients with PCOS took longer treatment duration to achieve CR (7.0 months vs. 5.4 months, p=0.006) and shorter time to relapse after CR (9.6 months vs. 17.6 months, p=0.040) compared with non-PCOS group. After adjusting for patient age, body mass index, PCOS, homeostasis model assessment-insulin resistance index, and serum testosterone levels, we found that body mass index ≥25 kg/m² (HR=0.583; 95% CI=0.365-0.932; p=0.024) and PCOS (HR=0.545; 95% CI=0.324-0.917; p=0.022) were significantly correlated with lower 16-week CR rate. PCOS was associated with lower 16-week CR rate, longer treatment duration and shorter recurrence interval in patients with AEH or EEC receiving fertility-preserving treatment.

Prognostic Significance of the CXCLs and Its Impact on the Immune Microenvironment in Ovarian Cancer

The chemokine (C-X-C motif) ligand (CXCL) family in tumor tissue is closely related to tumor growth, metastasis, and survival. However, the differential expression profile and prognostic value of the CXCLs in ovarian cancer (OC) have not been elucidated. Therefore, we studied the expression levels and mutations of CXCLs in OC patient in TCGA and various public databases. The expression differences of CXCLs in OC cancer tissues and normal tissues were compared through the Gene Expression Profiling Interactive Analysis (GEPIA) database. The effect of CXCLs on OC prognosis was analyzed using the Kaplan-Meier curves in GEPIA database. The impact of CXCLs on immune infiltration and clinicopathological outcomes in OC was assessed using the TIMER algorithm. Compared with normal tissues, we found that eight CXCLs were significantly differentially expressed in OC. The expression levels of CXCL9 ( P = 0.0201 ), CXCL11 ( P = 0.0385 ), and CXCL13 ( P = 0.0288 ) were significantly associated with tumor stage. CXCL13 was the only gene that significantly affected both disease-free survival (DFS) and overall survival (OS) in OC, and higher CXCL13 transcript levels implied longer DFS and OS. Although there was no significant impact on DFS, CXCL10 ( P = 0.0079 ) and CXCL11 ( P = 0.0011 ) expression levels had a significant effect on OS in OC. At the same time, CXCLs were significantly associated with several immune-infiltrating cells in OC tissues. The CXCLs were significantly associated with one or more immune-infiltrating cells in OC tissue. CXCL13 was differentially expressed in OC and significantly affected the prognosis of patients and was a potential marker of OC prognosis.

FOXP4-mediated induction of PTK7 activates the Wnt/β-catenin pathway and promotes ovarian cancer development

AbstractOvarian cancer (OV) poses a significant challenge in clinical settings due to its difficulty in early diagnosis and treatment resistance. FOXP4, belonging to the FOXP subfamily, plays a pivotal role in various biological processes including cancer, cell cycle regulation, and embryonic development. However, the specific role and importance of FOXP4 in OV have remained unclear. Our research showed that FOXP4 is highly expressed in OV tissues, with its elevated levels correlating with poor prognosis. We further explored FOXP4’s function through RNA sequencing and functional analysis in FOXP4-deficient cells, revealing its critical role in activating the Wnt signaling pathway. This activation exacerbates the malignant phenotype in OV. Mechanistically, FOXP4 directly induces the expression of protein tyrosine kinase 7 (PTK7), a Wnt-binding receptor tyrosine pseudokinase, which causes abnormal activation of the Wnt signaling pathway. Disrupting the FOXP4-Wnt feedback loop by inactivating the Wnt signaling pathway or reducing FOXP4 expression resulted in the reduction of the malignant phenotype of OV cells, while restoring PTK7 expression reversed this effect. In conclusion, our findings underscore the significance of the FOXP4-induced Wnt pathway activation in OV, suggesting the therapeutic potential of targeting this pathway in OV treatment.

Constructing a prediction model for lymph node metastasis in patients with incidental finding of endometrial cancer based on Fully-Connected Network

Rare studies focused on patients with incidental diagnosis of endometrial cancer (EC) after hysterectomy. We intended to construct a prediction model of lymph node metastasis (LNM) based on Fully-Connected Network (FC Network) for these patients. A total of 3,920 cases of EC that met the criteria from Obstetrics & Gynecology Hospital of Fudan University between January 2016 and February 2023 and 1995 cases from Fudan University Shanghai Cancer Center between January 2013 and October 2020 were retrospectively included for the construction of a predicting model which was based on FC Network. At the same time, 572 cases were prospectively collected for external validation. The sensitivity of the model was 0.946. Lympho-vascular space invasion, myometrial invasion, tumor grade, microcystic elongated and fragmented invasion, progesterone receptor, and cancer antigen 125 were used to construct a simplified nomogram. The area under the curve of the nomogram was 0.890 and 0.885 in validation and prospective cohorts, respectively. The model we proposed has good sensitivity and can be used to predict the risk of LNM in patients with incidentally found EC. The simplified nomogram can be used as a substitute in certain situations. Based on another study, the threshold of 5% and 25% can be used for risk stratification.

Self-Advocacy Among Women With Uterine Malignancies

Background Self-advocacy plays a crucial role in the mental health and treatment outcomes of oncology patients, particularly those with uterine malignancies. Despite its significance, research on the self-advocacy levels and influencing factors among Chinese patients with uterine malignancies remains limited. Objectives To assess the self-advocacy levels among Chinese patients with uterine malignancies and identify the demographic, psychological resilience, and decision self-efficacy factors that influence self-advocacy. Methods This cross-sectional study was conducted from March 1 to September 1, 2023, involving 220 inpatients with uterine malignancies from three tertiary hospitals in Shandong Province, China. Participants were recruited using convenience sampling and completed the General Information Questionnaire, Female Cancer Survivorship Self-advocacy Scale, Connor–Davidson Resilience Scale, and Decision Self-efficacy Scale. Results The average self-advocacy score among participants was 59.44 ± 10.14. Significant positive correlations were found between self-advocacy, psychological resilience, and decision self-efficacy. The random forest algorithm identified decision self-efficacy, psychological resilience, family average income, type of medical insurance, educational level, and residence as the six most important influencing factors, with the optimal model performance observed when lambda (λ) = 1.191. Multiple linear regression analysis further confirmed that decision self-efficacy, psychologic resilience, family average income, educational level, and residence were significant predictors of self-advocacy. Discussion The self-advocacy levels of Chinese patients with uterine malignancies were relatively low, with decision self-efficacy, psychological resilience, and socioeconomic factors significantly influencing their self-advocacy abilities. Future targeted interventions should focus on enhancing patients’ decision self-efficacy and psychological resilience, thereby guiding them to actively respond and participate in decision-making, ultimately improving self-advocacy among patients with uterine malignancies.

Cadonilimab Combined with Chemotherapy with or without Bevacizumab as First-Line Treatment in Recurrent or Metastatic Cervical Cancer (COMPASSION-13): A Phase 2 Study

Abstract Purpose: Immune checkpoint inhibitors (ICI) have been a potential treatment option for patients with cervical cancer in several clinical studies. We investigated the safety and efficacy of cadonilimab, a bispecific antibody targeting PD-1 and CTLA-4, plus standard therapy for the first-line treatment of R/M CC (recurrent and/or metastatic cervical cancer). Patients and Methods: Eligible patients were assigned to 3 cohorts: cohort A-15 (cadonilimab 15 mg/kg every 3 weeks (Q3W) plus chemotherapy), cohort A-10 (cadonilimb 10 mg/kg Q3W plus chemotherapy), and cohort B-10 (cadonilimab 10 mg/kg Q3W plus chemotherapy and bevacizumab). They received the corresponding treatments until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision. The primary objective was safety; the secondary endpoints included objective overall response (ORR), duration of response, disease control rate, progression-free survival, and overall survival. This study is registered with ClinicalTrials.gov (NCT04868708). Results: As of February 13, 2023, treatment-related adverse events (TRAE) occurred in 45 (100.0%) patients. Grade ≥3 TRAEs were reported in 33 (73.3%) patients. Immune-related adverse events (irAE) occurred in 29 (64.4%) patients and grade ≥3 irAEs were observed in 9 (20.0%) patients. Seven (15.6%) of 45 patients permanently discontinued cadonilimab treatment due to TRAEs. One death due to hemorrhagic shock occurred in cohort B-10. Among 44 patients who underwent at least one post-baseline tumor assessment, the ORR was 66.7% in cohort A-15, 68.8% in cohort A-10, 92.3% in cohort B-10, and 79.3% in cohorts A-10 and B-10 combined. Conclusions: Cadonilimab combined with standard therapy was acceptable, with encouraging antitumor activity in patients with R/M CC.

Progress in the Research of Cuproptosis and Possible Targets for Gynecological Cancers

ABSTRACT Cuproptosis is a regulated, copper‐dependent form of cell death driven by mitochondrial protein lipoylation and disruption of the tricarboxylic acid (TCA) cycle. Increasing evidence in gynecologic oncology indicates that copper transport, lipoate metabolism, and respiratory‐chain phosphorylation influence tumor fitness and treatment response. This review evaluates cuproptosis as a therapeutic hypothesis across gynaecologic cancers and outlines actionable targets and strategies based on this mechanism. Mechanistically, ferredoxin 1 (FDX1)‐mediated lipoylation enables copper excess to precipitate TCA enzyme‐dependent proteotoxic stress that is distinct from apoptosis and ferroptosis. Therapeutic concepts arising from this biology include modulation of copper flux with ionophores or chelators, inhibition of lipoic acid synthases, and disruption of mitochondrial proteostasis. Clinically, cuproptosis‐related transcriptional signatures and imaging markers of mitochondrial respiration may help stratify patients for combination regimens that incorporate poly (ADP‐ribose) polymerase inhibitors, anti‐angiogenic agents, or immune checkpoint blockade. By synthesizing available mechanistic and translational evidence and highlighting trials‐ready strategies, this review positions cuproptosis as a tractable, precision‐oriented pathway for ovarian, cervical, and endometrial cancers.