β-catenin is a potential prognostic biomarker in uterine sarcoma

β-catenin is a potential prognostic biomarker in uterine sarcoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article β-catenin is a potential prognostic biomarker in uterine sarcoma Ying Cai, Yunjia Wang, Ling Yang, Yue Huang, Min-Jun Chen, Chi Zhang, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4740736/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Uterine sarcoma (US) is an extremely rare and aggressive gynecologic malignancy with a poor overall survival (OS). The early screening and diagnosis of uterine sarcoma is still challenging, while efficient prognostic biomarker is currently lacking. In this study, we evaluated the expression of β-catenin in different US subtypes and the relationship between survival and clinicopathological characteristics by comparative analyses, then explored potential molecular mechanisms. Methods: We evaluated the expression of β-catenin in different US subtypes and the relationship between survival and clinicopathological characteristics by comparative analyses. Utilizing a Sweden microarray dataset (GSE119043, n=50) and a Suining clinical cohort (n=31), we analyzed β-catenin expression profiles and corresponding clinicopathological characteristics. To assess the expression level of β-catenin in US subtypes, we conducted immunohistochemistry (IHC). Survival analysis was used to assess the relationship between β-catenin expression and prognosis in US patients. Gene set enrichment analysis (GSEA) was performed to characterize the specific pathways involved in the β-catenin expression. Results: Immunohistochemistry indicated that the expression level of β-catenin significantly upregulated in the uterine sarcoma (US) group compared to both the normal uterine smooth muscle (UNSM) and uterine leiomyoma (ULM) groups (P<0.05). IHC also exhibited a significant difference in β-catenin expression levels in four pathological subtypes. Leiomyosarcoma (LMS) and high-grade endometrial stromal sarcoma (HG-ESS) suggested higher levels of β-catenin expression compared with adenosarcoma (AS) or low-grade endometrial stromal sarcoma (LG-ESS), but no statistically significant difference was found in box plot. Survival analysis showed that no significance between β-catenin expression levels and survival. Only tumor recurrence was significantly correlated with poor survival. Tumor type, lymphadenectomy, family history of malignancy and tumor recurrence remained significant predictors of overall survival (OS), while only tumor stage and tumor recurrence had prognostic significance for progression-free survival (PFS). Age, tumor size, menopausal status, CA125, adjuvant chemotherapy, and adjuvant radiotherapy, were not associated with survival (P>0.05). GSEA indicated that transcriptional misregulation in cancer, Wnt, AMPK, MAPK, PI3K, p53, Ras, and TNF signaling pathway were positively enriched in β-catenin high-expression group. Conclusion: β-catenin was highly expressed in uterine sarcoma and promising as a novel potential biomarker for diagnosis and prognosis. β-catenin Prognosis Uterine sarcoma Biomarker Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Introduction Uterine sarcoma (US) is one of the most aggressive gynecologic malignancies with an extremely poor overall prognosis, that accounts for approximately 1% of female genital tract malignancies and up to 7% of uterine malignancies [ 1 ]. Unfortunately, the mortality rate associated with this disease is quite high at approximately 30% [ 2 ]. Different from endometrial cancer, US derives from uterine mesenchymal cells and usually occurs after menopause [ 3 ]. Uterine sarcomas consist of several histological types, such as leiomyosarcoma (LMS), undifferentiated uterine sarcoma (UUS), adenosarcoma (AS), and endometrial stromal sarcoma (ESS), which including low-grade endometrial stromal sarcoma (LG-ESS) and high-grade endometrial stromal sarcoma (HG-ESS) [ 4 – 6 ]. Notably, carcinosarcoma is categorized as a subtype of endometrial cancer according to the International Federation of Gynecology and Obstetrics (FIGO) system staging and classification in 2023 [ 7 ]. Currently, the prognosis of US is still extremely poor due to the lack of standard therapeutic options. The 5-year survival rate ranges from 50–55% for early-stage uterine sarcomas to 8–12% for advanced cases [ 8 ]. Therefore, further insights are desperately needed to predict the outcome of uterine sarcomas to improve the prognosis. However, the discovery of new biomarkers and specific targeted therapies is still challenging owing to the low incidence of the disease. β-catenin, which is encoded by CTNNB1 (ENSG00000168036), serves as an intracellular signal transducer in the canonical Wnt signaling pathway [ 9 ]. Numerous studies have shown that the abnormal regulation of Wnt/β-catenin signaling is involved in the occurrence and development of various cancers [ 10 – 12 ]. As a key transduction intermediate, beta-catenin plays a crucial regulatory role in these cancers. Ovarian cancer cells have been shown to grow and metastasize by activating the Wnt signaling pathway [ 13 ]. The expression and membrane localization of β-cateninare associated with METTL3-promoted cell migration, invasion, and epithelial-to-mesenchymal transition (EMT) in cervical cancer [ 14 ]. Mutation of β-catenin exon 3 (87.0%; 47/54) was the main cause in young patients with low-grade and low-stage endometrioid endometrial carcinoma [ 9 ]. However, the expression of β-catenin in US remains unclear. In this study, to clarify the role of β-catenin in US, we explored the relationship between β-catenin expression and the prognosis of US. 2. Materials and Methods Data resource This study included two cohorts in total. The gene expression profiles and corresponding clinicopathological information were downloaded from the open databases, including a Sweden microarray dataset (GSE119043) from the Gene Expression Omnibus (GEO) ( https://www.ncbi.nlm.nih.gov/geo/ ), which contained data from 50 UUS patients. The above data are publicly available. A total of 31 diagnosed patients and clinicopathological information was collected from Suining Central Hospital (Department of Pathology) from May 2014 to January 2022. This study received approval from the Review Board of Suining Central Hospital (No. LLSLH20220051) and the Ethics Committee of Zunyi Medical University (No. 2020-1-013). The primary endpoint was overall survival (OS), defined as days from initial diagnosis to death or last follow-up. Progression-free survival (PFS) was defined as days from initial diagnosis to disease progression or death, whichever occurred first (or the date of last follow-up if progression or death had not yet occurred). Staging was assessed according to the International Federation of Gynecology and Obstetrics (FIGO) stage system [ 15 ]. Pathological inclusion criteria According to the National Comprehensive Cancer Network (NCCN) guidelines [ 16 ], The most common pathological types includes leiomyosarcoma (LMS), endometrial stromal sarcoma (ESS), undifferentiated uterine sarcoma (UUS) and adenosarcoma (AS). Notably, carcinosarcoma is categorized as a subtype of endometrial cancer according to the common newest classification. Therefore, we included patients with definitely pathological confirmation in this study, based on the fifth edition of the World Health Organization (WHO) Classification system of Tumors of Female Reproductive Organs in 2020 [ 17 ]. Patients with metastatic sarcoma from other gynecological sides or without complete information (a definitive pathological diagnosis, clinical findings, and loss of follow-up data, etc.) were excluded. Immunohistochemistry (IHC) In this study, we thoroughly reviewed the medical records of 31 patients with pathologically confirmed US, including 16 samples of LMS, 14 of ESS and 1 of AS, in the Department of Pathology of Suining Central Hospital [ 18 ]. Smooth muscle tissue of the uterine wall and leiomyoma tissue were also obtained if present. The expression of β-catenin was assessed by immunohistochemical method using a mouse-anti-human monoclonal antibody (MX043, MAIXIN, Fuzhou, Fujian). Tissue specimens were fixed with 10% formalin and preserved in paraffin. The paraffin-embedded blocks were sectioned continuously to a thickness of 4 µm and fixed on slides for immunohistochemical staining. Paraffin-embedded sections were dewaxed and then repaired using ethylenediaminetetraacetic acid (EDTA) antigen retrieval buffers. All IHC staining were performed using an automated immunostainer (VENTAN Bench Mark XT, Roche, Swiss). Human colorectal adenocarcinoma tissue was used as a positive control. The higher the expression content of β-catenin was, the greater was the distribution density and the stronger the positive result would be. β-catenin expression was evaluated using the H­ score, which is defined as the product of the staining intensity and the percentage of positively stained cells. The scoring system for staining intensity was as follows: 0 points for no staining, 1 point for light yellow, 2 points for brown‒yellow, and 3 points for brown. The percentage of positive cells was also considered, and the scores were as follows: 0 points, positive cells 5% or less; 1 point, positive cells between 6% and 25%; 2 points, positive cells between 26% and 50%; 3 points, positive cells between 51%-75%; and 4 points, positive cells greater than 75%. The resulting total scores were categorized as negative (0 points), weakly positive (1–4 points), moderately positive (5–8 points), and strongly positive (9–12 points). The scoring process was performed independently by two gynecologic pathologists using optical microscopy. The decision was made after discussion within the group if inconsistent. Gene set enrichment analysis Differential expressed genes (DEGs) were analyzed between β-catenin-low- and high-expression group in patients of Sweden microarray cohort using the R package DESeq2 (v1.44.0). Gene set enrichment analysis (GSEA) was then conducted using the R package clusterProfiler (v4.12.0) to explore the potential molecular mechanisms underlying the distinct gene expression [ 19 ]. Normalized enrichment score (NES) was calculated with gene set permutations set as 1000 times. Gene sets with |NES| > 1, adjusted p < 0.05, q < 0.05 were considered as significant enrichment. Statistical analysis The statistical analysis was performed using R (version 4.4.0). The distributions of categorical variables and continuous variables between cases and controls were performed using Pearson χ2 tests and Student’s t tests, respectively. Categorical data are presented as counts and percentages and were analyzed using the Chi-square test and Fisher’s exact test. The expression levels of β-catenin in patients were determined using the ggplot2 package. Based on the cut-off value of β-catenin expression, the patients were divided into high and low-β-catenin expression groups, Kaplan-Meier analysis was used to evaluate the relationship between overall survival and β-catenin expression level and pathological subtypes in Sweden microarray dataset (GSE119043) from GEO [ 20 ] and clinical cohort from Suining hospital. Univariate and multivariate cox proportional hazard regression analyses were used to explore β-catenin expression as an independent prognostic factor of US. P < 0.05 was considered statistically significant. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated. 3. Results Baseline characteristics According to the 2023 FIGO guidelines of the uterine sarcoma, we analyzed the clinical data collected from the patients' medical records, including age, histology, clinical and pathologic stage, and adjuvant chemotherapy (CT) or radiotherapy (RT). From an initial cohort of 56 patients, 31 patients were diagnosed with a definite pathological subtype of uterine sarcoma from Suining Central Hospital (Department of Pathology) [ 18 ]. The baseline characteristics of these patients from the clinical (Suining) cohort were presented in Table 1 . All patients involved in the study were female and categorized according to pathological type into groups of adenosarcoma (AS, n = 1), endometrial stromal sarcoma (ESS, n = 14) (including 12 low-grade ESS (LG-ESS) and 2 high-grade ESS (HG-ESS)), and leiomyosarcoma (LMS, n = 16). Nearly a half of them were over age 50. Most of them (n = 20, 64.52%) were premenopausal. Surgical approaches included total hysterectomy + bilateral salpingo-oophorectomy (TH + BSO), TH + BSO + pelvic lymphadenectomy (TH + BSO + PLA), TH + BSO + PLA + omentectomy, and TH + BSO + PLA + omentectomy + appendectomy. A total of 48.39% (n = 15) of all patients underwent lymphadenectomy. In addition, for adjuvant treatment, less than half of the patients (n = 13, 41.94%) received chemotherapy (CT) with doxorubicin and ifosfamide as the primary protocol, while the rest did not. Only six patients received radiotherapy (RT), while most of patients (n = 25, 80.65%) did not. Table 1 Baseline characteristics of 31 US patients from the Suining cohort (Line 145) Characteristics All Patients AS LG-ESS HG-ESS LMS P value (n = 31) (n = 1) (n = 12) (n = 2) (n = 16) Age at diagnosis(years), n (%) 0.389 ≤ 50 16(51.61) 1(6.25) 6(37.5) 0(0.0) 9(56.25) >50 15(48.39) 0(0.0) 6(40.0) 2(13.33) 7(46.67) Menopausal status, n (%) 0.872 Postmenopausal 11(35.48) 0(0.0) 4(36.36) 1(9.09) 6(54.55) Premenopausal 20(64.52) 1(5.0) 8(40.0) 1(5.0) 10(50.0) Symptoms, n (%) 0.118 Colporrhagia 9(29.03) 0(0.0) 4(44.44) 2(22.22) 3(33.33) Stomachache/bloating 7(22.58) 0(0.0) 2(28.57) 0(0.0) 5(71.43) Abdominal mass 10(32.26) 0(0.0) 4(40.0) 0(0.0) 6(60.0) Asymptomatic 5(16.13) 1(20.0) 2(40.0) 0(0.0) 2(40.0) Tumor size(cm), n (%) 0.072 ≤ 5 10(32.26) 1(10.0) 6(60.0) 1(10.0) 2(20.0) >5 21(67.74) 0(0.0) 6(28.57) 1(4.76) 14(66.67) CA125(U/ml), n (%) 0.541 35 8(25.81) 0(0.0) 2(25.0) 1(12.5) 5(62.5) Unknown 9(29.03) 0(0.0) 5(55.56) 0(0.0) 4(44.44) FIGO stage, n (%) 0.328 Ⅰ 22(70.97) 1(4.55) 10(45.45) 0(0.0) 11(50.0) Ⅱ 3(9.68) 0(0.0) 1(33.33) 1(33.33) 1(33.33) Ⅲ 2(6.45) 0(0.0) 1(50.0) 1(50.0) 0(0.0) Ⅳ 4(12.90) 0(0.0) 0(0.0) 0(0.0) 4(100.0) Surgical approach, n (%) 0.363 TH + BSO 16(51.61) 0(0.0) 8(50.0) 0(0.0) 8(50.0) TH + BSO + PLA 7(22.58) 1(14.29) 3(42.86) 2(28.57) 1(14.29) TH + BSO + PLA + omentectomy 5(16.13) 0(0.0) 1(20.0) 0(0.0) 4(80.0) TH + BSO + PLA + omentectomy + appendectomy 3(9.68) 0(0.0) 0(0.0) 0(0.0) 3(100.0) Lymphadenectomy, n (%) 0.25 Yes 15(48.39) 1(6.67) 4(26.67) 2(13.33) 8(53.33) No 16(51.61) 0(0.0) 8(50.0) 0(0.0) 8(50.0) Chemotherapy, n (%) 0.869 Yes 13(41.94) 0(0.0) 5(38.46) 1(7.69) 7(53.85) No 18(58.06) 1(5.56) 7(38.88) 1(5.56) 9(50.0) Radiotherapy, n (%) 0.802 Yes 6(19.35) 0(0.0) 2(33.33) 0(0.0) 4(66.67) No 25(80.65) 1(4.0) 10(40.0) 2(8.0) 12(48) 1 TH: Total hysterectomy; TH + BSO: Total hysterectomy + bilateral salpingo-oophorectomy; PLA: Pelvic lymphadenectomy. IHC Evaluation of β-catenin Immunohistochemistry was conducted to examine the expression of β-catenin in 31 full-face tissue sections obtained from US patients, including 24 paired samples of normal uterine smooth muscle (UNSM) and 5 paired samples of uterine leiomyoma (ULM). Positive expression of β-catenin was detected in the cell membrane and cytoplasm, appearing as light yellow, brownish yellow or dark brown particles. All specimens from US patients showed varying levels of positivity, ranging from moderate to strong. As shown in Fig. 1 a, among 5 paired samples, the expression level of β-catenin exhibited a significant increase in the US group compared to both the UNSM and ULM groups (P < 0.05, both) and in the ULM group compared to the UNSM group (P < 0.05) (Fig. 1 b). Furthermore, among 24 paired samples, similar results were obtained both in the tumor tissues from US group compared to the normal tissues from UNSM group(P < 0.001) (Fig. 1 c). In different pathological types, immunohistochemistry revealed a significant difference in β-catenin protein expression levels among AS, LMS, LG-ESS and HG-ESS (Fig. 2 a). The expression of β-catenin in AS showed moderate positivity and was significantly lower than that in LMS. Furthermore, the expression of β-catenin in HG-ESS was substantially up-regulated compared with LG-ESS, although there were only two patients. Obviously, the findings indicated that LMS and HG-ESS patients exhibited the higher levels of β-catenin expression when compared with other types. However, the box plot showed there was no significance in β-catenin expression among AS, LMS, LG-ESS and HG-ESS (Fig. 2 b, P > 0.05). Survival analysis Survival analysis indicated that with high β-catenin expression levels had no significance with OS (HR, 2.046; 95%CI: 0.4299–9.737; P = 0.36; Fig. 3 a) and PFS (HR, 0.5296; 95%CI: 0.1544–1.817; P = 0.30; Fig. 3 b) in Suining cohort. The median OS in the high- or low-β-catenin expression group were not reached (NR). The median PFS in low-β-catenin group was not reached (NR), indicating a longer but not statistically significant survival compared to the median PFS of high expression group (61.73 months VS 34.75 months). The similar results of OS were obtained in 50 UUS patients from the Sweden microarray cohort (HR, 0.5724; 95%CI: 0.2688–1.219; P = 0.14; Fig. 3 c), while low-β-catenin expression group also showed a longer but no statistical significance median OS compared to the high expression group (56.17 months VS 9.60 months). Univariate and multivariate cox regression analysis Univariate and multivariate cox proportional hazard regression analyses were carried out with US patients from the Sweden microarray cohort. The univariate analysis indicated that copy number variation (CNV) group (HR = 2.04; 95% CI: 1.05–3.96; P = 0.034), hormone receptor expression (HR, 0.21; 95%CI: 0.09–0.48; P < 0.001), mitotic index group (HR, 2.33; 95% CI: 1.21–4.50; P = 0.012) and nuclear atypia (HR, 1.96; 95% CI: 1.01–3.80; P = 0.046) were significantly associated with OS in US patients. Multivariate analysis showed hormone receptor expression (HR, 0.24; 95% CI: 0.10–0.60; P = 0.002), and mitotic index group (HR, 2.70; 95% CI: 1.21–6.05; P = 0.016) still remained the same results (Supplementary Table S1 ). However, we noted no substantial correlation between CTNNB1 expression and OS (HR, 1.75; 95% CI: 0.82–3.72; P = 0.148;). Additional clinical indicators, including cell density, displayed no relationship with OS (P > 0.05). The findings were presented in Table 2 . Table 2 Univariate cox analysis of OS in US patients from the Sweden microarray cohort (Line 206) Features Univariate analysis HR 95% CI p value Cell density (High vs. Low) 0.96 0.51–1.80 0.891 CNV group (High vs. Low) 2.04 1.05–3.96 0.034 Hormone receptor expression (Positive vs. Negative) 0.21 0.09–0.48 <0.001 Mitotic index group (High vs. Low) 2.33 1.21–4.50 0.012 Nuclear atypia (Pleomorphic vs. Uniform) 1.96 1.01–3.80 0.046 RNA group (Developmental vs. Others) 0.70 0.37–1.32 0.270 CTNNB1 expression (High vs. Low) 1.75 0.82–3.72 0.148 Furthermore, we conducted univariate and multivariate cox proportional hazard regression analyses of OS and PFS in US patients from the clinical cohort. Our analysis demonstrated that tumor type, lymphadenectomy, family history of malignancy and tumor recurrence remained significant predictors of OS, while only tumor stage and tumor recurrence were associated with PFS (P < 0.05, Table 3 – 4 ). Univariate analyses demonstrated that only tumor recurrence (HR, 44.22; 95% CI: 5.39-363.12; P < 0.001) was significantly associated with OS and PFS in US patients. Nevertheless, the results indicated an absent relationship between β-catenin expression and OS (HR, 1.53; 95% CI: 0.40–5.93; P = 0.383) or PFS (HR, 2.24; 95% CI: 0.46–10.82; P = 0.317) in US patients, consistent with prior study from the Sweden cohort. Moreover, other clinical variables did not influence OS and PFS (P > 0.05, Supplementary Table S2-S3). Table 3 Univariate cox analysis of PFS in US patients from the Suining cohort (Line 212) Clinicopathological features Univariate analysis HR 95% CI p value Age (≤ 50 vs. >50) 1.59 0.43–5.96 0.490 Tumor stage (I/II vs. III/IV) 7.62 1.97–29.53 0.003 Menopausal status (Postmenopausal vs. Premenopausal) 0.50 0.10–2.40 0.384 Tumor size (≤ 5 vs. >5) 2.13 0.44–10.26 0.348 CA125 (35) 2.03 0.78–5.29 0.147 Lymphadenectomy (Yes vs. No) 4.22 0.88–20.36 0.073 Family history of malignancy (Yes vs. No) 9.22 0.96–88.69 0.055 Tumor recurrence (Yes vs. No) 44.22 5.39-363.12 <0.001 Adjuvant chemotherapy (Yes vs. No) 1.89 0.50–7.07 0.344 Adjuvant radiotherapy (Yes vs. No) 1.12 0.23–5.43 0.886 β-catenin expression (High vs. Low) 2.24 0.46–10.82 0.317 Table 4 Univariate cox analysis of OS in US patients from the Suining cohort (Line 212) Clinicopathological features Univariate analysis HR 95% CI p value Age (≤ 50 vs. >50) 3.05 0.79–11.80 0.107 Tumor stage (I/II vs. III/IV) 3.52 0.99–12.54 0.052 Menopausal status (Postmenopausal vs. Premenopausal) 1.18 0.33–4.20 0.798 Tumor size (≤ 5 vs. >5) 1.42 0.37–5.53 0.610 CA125 (35) 2.31 0.94–5.70 0.068 Tumor type (AS + LG-ESS vs. LMS + HG-ESS) 8.94 1.12–71.02 0.038 Lymphadenectomy (Yes vs. No) 4.97 1.05–23.45 0.043 Family history of malignancy (Yes vs. No) 14.13 1.28-156.01 0.031 Tumor recurrence (Yes vs. No) 12.46 3.09–50.27 <0.001 Adjuvant chemotherapy (Yes vs. No) 1.61 0.46–5.57 0.453 Adjuvant radiotherapy (Yes vs. No) 0.47 0.06–3.75 0.480 β-catenin expression (High vs. Low) 1.53 0.40–5.93 0.538 GSEA to get first hints about the specific pathways involved in β-catenin Based on the potential prognostic significance of β-catenin expression level in uterine sarcoma, we investigated the underlying biological mechanisms. Differential expressed genes (DEGs) were analyzed between β-catenin high- and low-expression group in patients from Sweden cohort, and gene set enrichment analysis (GSEA) was then performed to characterize the specific pathways that involved in the β-catenin expression. The positively enriched gene sets in the β-catenin-high expression group included AMP-activated protein kinase (AMPK) signaling pathway, endometrial cancer, mito-gen-activated protein kinase (MAPK) signaling pathway, protein 53 (p53) signaling pathway, phosphatidylinositol-3-kinase/protein kinase B (PI3K-Akt) signaling pathway, rat sarcoma (Ras) signaling pathway, tumor necrosis factor (TNF) signaling pathway, Wnt signaling pathway, and transcriptional misregulation in cancer. On the other hand, ascorbate and aldarate metabolism, cytokine-cytokine receptor interaction, pentose and glucuronate interconventions, retinol metabolism, steriod hormone biosynthesis, taurine and hypotaurine metabolism, were negatively enriched in the β-catenin-high-expression group (Fig. 4 , Supplementary Table S4). 4. Discussion Uterine sarcomas are rare and aggressive gynecologic malignancies, characterized by a relatively high recurrence rate. The prognosis of uterine sarcoma remains poor, with a mortality rate of up to 30% due to its highly aggressive nature [ 21 ]. There are few effective prognostic biomarkers or models for improving the clinical outcomes of US patients. In general, US patients always diagnosed after menopause [ 3 ]. Interestingly, a significant number of women remained in the premenopausal phase in our study. This finding hints at an evolving trend towards rejuvenation worth monitoring. Previous research proposed that specific fusion proteins in LG-ESS contribute to overexpression of Wnt ligands with subsequent activation of Wnt signaling pathway and formation of an active β-catenin/Lef1 transcriptional complex [ 22 ]. In this study, we confirmed that the expression level of β-catenin significantly upregulated in the US group compared to both the UNSM and ULM groups. Furthermore, immunohistochemistry exhibited a significant difference in β-catenin expression levels in four pathological subtypes. LMS and HG-ESS exhibited higher levels of β-catenin expression compared with AS or LG-ESS, but no statistically significant difference was displayed. Survival analyses showed that no significance between β-catenin expression levels and OS or PFS. The late endpoint events of patients (reaching beyond follow-up cut-off), may affect the results. As indicated by the above results, β-catenin was closely correlated with uterine sarcoma. Based on our study, we discovered only tumor recurrence was significantly correlated with poor survival. Tumor type, lymphadenectomy, family history of malignancy and tumor recurrence remained significant predictors of OS, while only tumor stage and tumor recurrence had prognostic significance for PFS. We respectfully diverged from Wang et al.'s claim on the correlation between tumor size and survival (OS and PFS) [ 23 ]. Other clinical variables, such as age, menopausal status, CA125, adjuvant chemotherapy, and adjuvant radiotherapy, did not influence survival (P > 0.05). Despite lacking survival correlations, elevated circulating CA125 levels were noted in nearly a half of patients. Focusing on these patients may prompt potential benefits for diagnosis. Currently, there was no standard therapeutic options for uterine sarcoma, with varying perspectives on surgical method. The cornerstone of the approach to US is hysterectomy and bilateral salpingo-oophorectomy (BSO) [ 24 ]. It was reported that incomplete surgery was associated with poor prognosis [ 25 ]. Our research suggested that lymphadenectomy influenced OS in uterine sarcoma patients, aligning well with Machida's work [ 26 ]. Additionally, we found that adjuvant chemotherapy or radiotherapy was no significance with survival, consistent with prior research results [ 27 , 28 ]. Whether radiotherapy or chemotherapy should be given after surgery is still debated. In this study, we first explored β-catenin expression level and its potential role as an effective predictive biomarker for prognosis prediction of uterine sarcoma. We found that β-catenin was highly expressed in US, compared with UNSM and ULM, while survival analyses and cox regression analyses in the Sweden and Suining cohorts showed that there was no significant correlation between β-catenin expression level and the prognosis of US patients. These findings suggested that β-catenin was highly expressed in uterine sarcoma and would be promising as a novel potential biomarker for the diagnosis and prognosis of uterine sarcoma. Wnt/β-catenin aberrant activation is linked with increased cancer occurrence, tumor progression, adverse prognosis development, and cancer-related mortality risk in human cancers. Altered β-catenin is thought to drive tumorigenesis in multiple cancers [ 29 ], notably colorectal cancer [ 30 ] and endometrial carcinoma (EC) [ 31 ]. Somatic mutation in coded gene hotspots or mutational inactivation of Adenomatous polyposis coli (APC) are two main mechanisms existed in endometrial carcinoma for increasing β-catenin levels. Tumors with β-catenin coded gene hotspot mutations exhibited higher Wnt signaling pathway activity, characterized by increased expression of the key protein β-catenin within the pathway. β-catenin, APC, Axin (axin inhibitor), CK-1α protein (casein kinase 1α protein) and GSK-3β protein (glycogen synthase kinase 3β protein) formed the destruction complex that captured β-catenin by phosphorylating CK1 and GSK3, thus activating the process of β-catenin degradation. The mutational inactivation of APC leaded to the accumulation of β-catenin [ 12 , 32 ]. In our study, the positive enrichment of Wnt signaling pathway in the β-catenin high-expression group supported that β-catenin would be a satisfactory tool to predict prognosis in uterine sarcoma patients. Several tumor progression related gene sets, including Wnt, TNF, AMPK, MAPK, p53, PI3K-Akt, Ras signaling pathway, endometrial cancer, and transcriptional misregulation in cancer, were the potential predominant molecular pathways implicated in the uterine sarcoma development. For example, YWHAE-NUTM2 regulated cyclin D1 expression and cell proliferation by dysregulating RAF/MEK/MAPK and Hippo/YAP-TAZ signaling pathways in HG-ESS [ 33 ]. Intriguingly, autophagy inhibitor 3-Methyladenine (3-MA) potentiated the antitumor efficacy of apatinib in uterine sarcoma by stimulating PI3K/Akt/mTOR pathway [ 34 ]. On the other hand, the results suggested that several negatively enriched pathways in β-catenin low-expression group mainly involved in metabolism and hormone biosynthesis. Taurine not only inhibited cancer cell proliferation but also induced apoptosis in certain cancers by differential regulating proapoptotic and antiapoptotic proteins [ 30 ]. Taurine and hypotaurine metabolism pathway was continually disturbed during the progression of gastric carcinogenesis (GCG), potentially due to abnormal energy supply for tumor cell proliferation and growth [ 31 ]. In endometrial cancer (EC), Kaempferol affected multiple estrogen metabolism pathways by regulating HSD17B1 and HSD17B1-associated genes, which were involved in steroid hormone biosynthesis and regulation of hormone levels [ 32 ]. The above pathways were the potential crucial mechanisms to explore the role of β-catenin in uterine sarcoma genesis and progression. Certainly, our study has limitation. Given a total of only 50 patients for Sweden microarray cohort and 31 patients for Suining cohort, it is worth noting that the sample size might limit our ability to draw significant conclusions. Going forward, we plan to keep long-term follow-up for the patients and further explore the mechanism of β-catenin in the development of uterine sarcoma. 5. Conclusions β-catenin was highly expressed in uterine sarcoma and would be promising as a novel potential biomarker for the diagnosis and prognosis of uterine sarcoma. Declarations Supplementary Materials: The following supporting information can be downloaded at: www.mdpi.com/xxx/s1, Table S1: Multivariate cox analysis of OS in US patients from the Sweden microarray cohort; Table S2: Multivariate cox analysis of PFS in US patients from the Suining cohort; Table S3: Multivariate cox analysis of OS in US patients from the Suining cohort. Author Contributions: Conceptualization, Jian-Guo Zhou; Data curation, Yunjia Wang, Ling Yang and Yue Huang; Formal analysis, Min-Jun Chen and Chi Zhang; Funding acquisition, Hu Ma and Jian-Guo Zhou; Methodology, Jian-Guo Zhou; Project administration, Jian-Guo Zhou; Resources, Jian-Guo Zhou; Supervision, Jian-Guo Zhou; Visualization, Ying Cai; Writing – original draft, Ying Cai; Writing – review & editing, Su-Han Jin, Benjamin Frey, Udo Gaipl, Hu Ma and Jian-Guo Zhou. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the National Natural Science Foundation of China, Grant No. 82060475; Chunhui program of the Chinese Ministry of Education, Grant No. HZKY20220231; the Natural Science Foundation of Guizhou Province, Grant No. ZK2022-YB632; Youth Talent Project of Guizhou Provincial Department of Education, Grant No. QJJ2022-224; China Lung Cancer Immunotherapy Research Project, Excellent Young Talent Cultivation Project of Zunyi City, Zunshi Kehe HZ (2023) 142; Future Science and Technology Elite Talent Cultivation Project of Zunyi Medical University, ZYSE-2023-02; Collaborative Innovation Center of Chinese Ministry of Education, Grant No. 2020-39. Institutional Review Board Statement: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Review Board of Suining Central Hospital (No. LLSLH20220051) and the Ethics Committee of Zunyi Medical University (No. 2020-1-013). Informed consent was obtained from each participant. Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Data Availability Statement: The data for uterine sarcoma in GSE119043 are available at the Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) portal. Analysis tools are listed in Methods. The data for Suining cohort presented in this article are not readily available because the data are part of an ongoing study, due to necessary secrecy. Requests to access the datasets should be directed to the corresponding author. Conflicts of Interest: The authors declare no conflicts of interest. References D'Angelo E, Prat J: Uterine sarcomas: a review. Gynecol Oncol 2010, 116: 131-139. Matsuo K, Takazawa Y, Ross MS, Elishaev E, Podzielinski I, Yunokawa M, Sheridan TB, Bush SH, Klobocista MM, Blake EA, et al: Significance of histologic pattern of carcinoma and sarcoma components on survival outcomes of uterine carcinosarcoma. Ann Oncol 2016, 27: 1257-1266. Roberts ME, Aynardi JT, Chu CS: Uterine leiomyosarcoma: A review of the literature and update on management options. Gynecol Oncol 2018, 151: 562-572. Mbatani N, Olawaiye AB, Prat J: Uterine sarcomas. Int J Gynaecol Obstet 2018, 143 Suppl 2: 51-58. Plentz T, Candido EC, Dias LF, Toledo MCS, Vale DB, Teixeira JC: Diagnosis, treatment and survival of uterine sarcoma: A retrospective cohort study of 122 cases. Mol Clin Oncol 2020, 13: 81. Zhou JG, Zhao HT, Jin SH, Tian X, Ma H: Identification of a RNA-seq-based signature to improve prognostics for uterine sarcoma. Gynecol Oncol 2019, 155: 499-507. Berek JS, Matias-Guiu X, Creutzberg C, Fotopoulou C, Gaffney D, Kehoe S, Lindemann K, Mutch D, Concin N, Endometrial Cancer Staging Subcommittee FWsCC: FIGO staging of endometrial cancer: 2023. J Gynecol Oncol 2023, 34: e85. Gadducci A, Cosio S, Romanini A, Genazzani AR: The management of patients with uterine sarcoma: a debated clinical challenge. Crit Rev Oncol Hematol 2008, 65: 129-142. Liu Y, Patel L, Mills GB, Lu KH, Sood AK, Ding L, Kucherlapati R, Mardis ER, Levine DA, Shmulevich I, et al: Clinical significance of CTNNB1 mutation and Wnt pathway activation in endometrioid endometrial carcinoma. J Natl Cancer Inst 2014, 106 . Nejak-Bowen KN, Monga SP: Beta-catenin signaling, liver regeneration and hepatocellular cancer: sorting the good from the bad. Semin Cancer Biol 2011, 21: 44-58. McCleary NJ, Sato K, Nishihara R, Inamura K, Morikawa T, Zhang X, Wu K, Yamauchi M, Kim SA, Sukawa Y, et al: Prognostic Utility of Molecular Factors by Age at Diagnosis of Colorectal Cancer. Clin Cancer Res 2016, 22: 1489-1498. Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, Zhou Z, Shu G, Yin G: Wnt/beta-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther 2022, 7: 3. Jimeno A, Gordon M, Chugh R, Messersmith W, Mendelson D, Dupont J, Stagg R, Kapoun AM, Xu L, Uttamsingh S, et al: A First-in-Human Phase I Study of the Anticancer Stem Cell Agent Ipafricept (OMP-54F28), a Decoy Receptor for Wnt Ligands, in Patients with Advanced Solid Tumors. Clin Cancer Res 2017, 23: 7490-7497. Li J, Xie G, Tian Y, Li W, Wu Y, Chen F, Lin Y, Lin X, Wing-Ngor Au S, Cao J, et al: RNA m(6)A methylation regulates dissemination of cancer cells by modulating expression and membrane localization of beta-catenin. Mol Ther 2022, 30: 1578-1596. Prat J: FIGO staging for uterine sarcomas. Int J Gynaecol Obstet 2009, 104: 177-178. Abu-Rustum NR, Yashar CM, Bradley K, Campos SM, Chino J, Chon HS, Chu C, Cohn D, Crispens MA, Damast S, et al: NCCN Guidelines(R) Insights: Uterine Neoplasms, Version 3.2021. J Natl Compr Canc Netw 2021, 19: 888-895. Cree IA, White VA, Indave BI, Lokuhetty D: Revising the WHO classification: female genital tract tumours. Histopathology 2020, 76: 151-156. Yang L, Cai Y, Wang Y, Huang Y, Zhang C, Ma H, Zhou JG: Fibroblast Growth Factor 23 is a Potential Prognostic Biomarker in Uterine Sarcoma. Technol Cancer Res Treat 2024, 23: 15330338241245924. Zhou JG, Zeng Y, Wang H, Jin SH, Wang YJ, He S, Frey B, Fietkau R, Hecht M, Ma H, et al: Identification of an endogenous retroviral signature to predict anti-PD1 response in advanced clear cell renal cell carcinoma: an integrated analysis of three clinical trials. Ther Adv Med Oncol 2022, 14: 17588359221126154. Gultekin O, Gonzalez-Molina J, Hardell E, Moyano-Galceran L, Mitsios N, Mulder J, Kokaraki G, Isaksson A, Sarhan D, Lehti K, Carlson JW: FOXP3+ T cells in uterine sarcomas are associated with favorable prognosis, low extracellular matrix expression and reduced YAP activation. NPJ Precis Oncol 2021, 5: 97. Huss A, Klar M, Hasanov MF, Juhasz-Boss I, Bossart M: Prognostic factors and survival of patients with uterine sarcoma: a German unicenter analysis. Arch Gynecol Obstet 2023, 307: 927-935. Przybyl J, Kidzinski L, Hastie T, Debiec-Rychter M, Nusse R, van de Rijn M: Gene expression profiling of low-grade endometrial stromal sarcoma indicates fusion protein-mediated activation of the Wnt signaling pathway. Gynecol Oncol 2018, 149: 388-393. Wang F, Dai X, Chen H, Hu X, Wang Y: Clinical characteristics and prognosis analysis of uterine sarcoma: a single-institution retrospective study. BMC Cancer 2022, 22: 1050. Giannini A, Golia D'Auge T, Bogani G, Lagana AS, Chiantera V, Vizza E, Muzii L, Di Donato V: Uterine sarcomas: A critical review of the literature. Eur J Obstet Gynecol Reprod Biol 2023, 287: 166-170. Kikuchi A, Yoshida H, Tsuda H, Nishio S, Suzuki S, Takehara K, Kino N, Sumi T, Kato K, Yokoyama M, et al: Clinical characteristics and prognostic factors of endometrial stromal sarcoma and undifferentiated uterine sarcoma confirmed by central pathologic review: A multi-institutional retrospective study from the Japanese Clinical Oncology Group. Gynecol Oncol 2023, 176: 82-89. Machida H, Nathenson MJ, Takiuchi T, Adams CL, Garcia-Sayre J, Matsuo K: Significance of lymph node metastasis on survival of women with uterine adenosarcoma. Gynecol Oncol 2017, 144: 524-530. Hosh M, Antar S, Nazzal A, Warda M, Gibreel A, Refky B: Uterine Sarcoma: Analysis of 13,089 Cases Based on Surveillance, Epidemiology, and End Results Database. Int J Gynecol Cancer 2016, 26: 1098-1104. Galaal K, van der Heijden E, Godfrey K, Naik R, Kucukmetin A, Bryant A, Das N, Lopes AD: Adjuvant radiotherapy and/or chemotherapy after surgery for uterine carcinosarcoma. Cochrane Database Syst Rev 2013, 2013: CD006812. Gao C, Wang Y, Broaddus R, Sun L, Xue F, Zhang W: Exon 3 mutations of CTNNB1 drive tumorigenesis: a review. Oncotarget 2018, 9: 5492-5508. Wong NA, Pignatelli M: Beta-catenin--a linchpin in colorectal carcinogenesis? Am J Pathol 2002, 160: 389-401. Parrish ML, Broaddus RR, Gladden AB: Mechanisms of mutant beta-catenin in endometrial cancer progression. Front Oncol 2022, 12: 1009345. Dou Y, Kawaler EA, Cui Zhou D, Gritsenko MA, Huang C, Blumenberg L, Karpova A, Petyuk VA, Savage SR, Satpathy S, et al: Proteogenomic Characterization of Endometrial Carcinoma. Cell 2020, 180: 729-748 e726. Ou WB, Lundberg MZ, Zhu S, Bahri N, Kyriazoglou A, Xu L, Chen T, Marino-Enriquez A, Fletcher JA: YWHAE-NUTM2 oncoprotein regulates proliferation and cyclin D1 via RAF/MAPK and Hippo pathways. Oncogenesis 2021, 10: 37. Chen S, Yao L: Autophagy inhibitor potentiates the antitumor efficacy of apatinib in uterine sarcoma by stimulating PI3K/Akt/mTOR pathway. Cancer Chemother Pharmacol 2021, 88: 323-334. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4740736","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":336822435,"identity":"a0e911ea-4f7d-4d4a-83a3-e29d216d416f","order_by":0,"name":"Ying Cai","email":"","orcid":"","institution":"The Second Affiliated Hospital of Zunyi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Cai","suffix":""},{"id":336822436,"identity":"a48972df-0797-44e8-8f8d-72404e123e41","order_by":1,"name":"Yunjia Wang","email":"","orcid":"","institution":"The Second Affiliated Hospital of Zunyi 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Zhou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7ElEQVRIiWNgGAWjYBACxmYYSwKIP0CYBsRrYZxBjBYEAGph5iFGC3M787OHX9tsGORnNx+TtvmzLbGBvXmbBEPNHTwOYzM3lm1LY2CccyxNOofndmIDz7EyCYZjz/D5xUxasu0wA7NEjpl0jgRQC5AhwdhwGI8W9m9gLWwgLRYGQC3ybwhp4TGT/AjUwgPSwpAAsoWHoJYyaYZzaTwSEmnJlj0Hbhu38aQVWyQcw63FsP/4NskfZTZy8jOSD9748ee2bD/74Y03PtTg0dIAiQ4euAgbiEjAqYGBQR7kuB94FIyCUTAKRsEoYAAAEelKnoOLyysAAAAASUVORK5CYII=","orcid":"","institution":"The Second Affiliated Hospital of Zunyi Medical University","correspondingAuthor":true,"prefix":"","firstName":"Jian-Guo","middleName":"","lastName":"Zhou","suffix":""}],"badges":[],"createdAt":"2024-07-15 04:45:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4740736/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4740736/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":62223310,"identity":"6f3cceba-f81c-4dc8-af15-40ca011c03ae","added_by":"auto","created_at":"2024-08-11 12:48:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2311837,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(a) \u003c/strong\u003eIHC indicated the expression levels of β-catenin in the UNSM, ULM and US groups. \u003cstrong\u003e(b)\u003c/strong\u003e The box plot showed β-catenin expression in US, ULM, and UNSM among 5 paired samples.\u003cstrong\u003e (c)\u003c/strong\u003e The box plot showed β-catenin expression in and UNSM (normal) and US (tumor) among 24 paired samples.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4740736/v1/f7cba363ba4cb99b1330fe11.png"},{"id":62222938,"identity":"5be593b0-1cd6-470d-8374-7bd8e0259f5a","added_by":"auto","created_at":"2024-08-11 12:40:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1143129,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(a) \u003c/strong\u003eIHC indicated the expression levels of β-catenin in different pathological types of US. \u003cstrong\u003e(b)\u003c/strong\u003e The box plot displayed β-catenin protein expression in different pathological subtypes of US.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4740736/v1/25e8e68a59642117e8549d4c.png"},{"id":62222936,"identity":"35c28834-027d-43e4-84e8-8d839a3a0b0e","added_by":"auto","created_at":"2024-08-11 12:40:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":320026,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A) \u003c/strong\u003eResult of GSEA showed the positively enriched gene sets in the β-catenin-high expression group. (GSEA, gene set enrichment analysis.) \u003cstrong\u003e(B) \u003c/strong\u003eResult of GSEA displayed the negatively enriched gene sets in the β-catenin-low expression group.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4740736/v1/7b64ed2beaa1c3d72561c3b6.png"},{"id":62222941,"identity":"f0feaca4-a466-48e2-8b9a-40add84a488a","added_by":"auto","created_at":"2024-08-11 12:40:58","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":422717,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A) \u003c/strong\u003eResult of GSEA showed the positively enriched gene sets in the β-catenin-high expression group. (GSEA, gene set enrichment analysis.) \u003cstrong\u003e(B) \u003c/strong\u003eResult of GSEA displayed the negatively enriched gene sets in the β-catenin-low expression group.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4740736/v1/8f4f77bde369c754c3b77de9.png"},{"id":76979656,"identity":"641a0fe3-1a66-4803-a0cf-38651246ae08","added_by":"auto","created_at":"2025-02-24 00:46:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":7282662,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4740736/v1/8724ed6f-6bcd-4318-b716-59fa1f4a9416.pdf"},{"id":62222940,"identity":"b87861ef-fcee-4f5c-8870-798135b9fba7","added_by":"auto","created_at":"2024-08-11 12:40:58","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":66549,"visible":true,"origin":"","legend":"","description":"","filename":"cateninsupplementalFilesWJSO.docx","url":"https://assets-eu.researchsquare.com/files/rs-4740736/v1/2f9227607e363461c8febbb9.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"β-catenin is a potential prognostic biomarker in uterine sarcoma","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eUterine sarcoma (US) is one of the most aggressive gynecologic malignancies with an extremely poor overall prognosis, that accounts for approximately 1% of female genital tract malignancies and up to 7% of uterine malignancies [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Unfortunately, the mortality rate associated with this disease is quite high at approximately 30% [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Different from endometrial cancer, US derives from uterine mesenchymal cells and usually occurs after menopause [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Uterine sarcomas consist of several histological types, such as leiomyosarcoma (LMS), undifferentiated uterine sarcoma (UUS), adenosarcoma (AS), and endometrial stromal sarcoma (ESS), which including low-grade endometrial stromal sarcoma (LG-ESS) and high-grade endometrial stromal sarcoma (HG-ESS) [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Notably, carcinosarcoma is categorized as a subtype of endometrial cancer according to the International Federation of Gynecology and Obstetrics (FIGO) system staging and classification in 2023 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Currently, the prognosis of US is still extremely poor due to the lack of standard therapeutic options. The 5-year survival rate ranges from 50\u0026ndash;55% for early-stage uterine sarcomas to 8\u0026ndash;12% for advanced cases [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Therefore, further insights are desperately needed to predict the outcome of uterine sarcomas to improve the prognosis. However, the discovery of new biomarkers and specific targeted therapies is still challenging owing to the low incidence of the disease.\u003c/p\u003e\u003cp\u003eβ-catenin, which is encoded by CTNNB1 (ENSG00000168036), serves as an intracellular signal transducer in the canonical Wnt signaling pathway [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Numerous studies have shown that the abnormal regulation of Wnt/β-catenin signaling is involved in the occurrence and development of various cancers [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. As a key transduction intermediate, beta-catenin plays a crucial regulatory role in these cancers. Ovarian cancer cells have been shown to grow and metastasize by activating the Wnt signaling pathway [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The expression and membrane localization of β-cateninare associated with METTL3-promoted cell migration, invasion, and epithelial-to-mesenchymal transition (EMT) in cervical cancer [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Mutation of β-catenin exon 3 (87.0%; 47/54) was the main cause in young patients with low-grade and low-stage endometrioid endometrial carcinoma [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, the expression of β-catenin in US remains unclear. In this study, to clarify the role of β-catenin in US, we explored the relationship between β-catenin expression and the prognosis of US.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e\u003cb\u003eData resource\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis study included two cohorts in total. The gene expression profiles and corresponding clinicopathological information were downloaded from the open databases, including a Sweden microarray dataset (GSE119043) from the Gene Expression Omnibus (GEO) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/geo/\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/geo/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), which contained data from 50 UUS patients. The above data are publicly available. A total of 31 diagnosed patients and clinicopathological information was collected from Suining Central Hospital (Department of Pathology) from May 2014 to January 2022. This study received approval from the Review Board of Suining Central Hospital (No. LLSLH20220051) and the Ethics Committee of Zunyi Medical University (No. 2020-1-013).\u003c/p\u003e\u003cp\u003eThe primary endpoint was overall survival (OS), defined as days from initial diagnosis to death or last follow-up. Progression-free survival (PFS) was defined as days from initial diagnosis to disease progression or death, whichever occurred first (or the date of last follow-up if progression or death had not yet occurred). Staging was assessed according to the International Federation of Gynecology and Obstetrics (FIGO) stage system [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003ePathological inclusion criteria\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAccording to the National Comprehensive Cancer Network (NCCN) guidelines [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], The most common pathological types includes leiomyosarcoma (LMS), endometrial stromal sarcoma (ESS), undifferentiated uterine sarcoma (UUS) and adenosarcoma (AS). Notably, carcinosarcoma is categorized as a subtype of endometrial cancer according to the common newest classification. Therefore, we included patients with definitely pathological confirmation in this study, based on the fifth edition of the World Health Organization (WHO) Classification system of Tumors of Female Reproductive Organs in 2020 [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Patients with metastatic sarcoma from other gynecological sides or without complete information (a definitive pathological diagnosis, clinical findings, and loss of follow-up data, etc.) were excluded.\u003c/p\u003e\u003cp\u003e\u003cb\u003eImmunohistochemistry (IHC)\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIn this study, we thoroughly reviewed the medical records of 31 patients with pathologically confirmed US, including 16 samples of LMS, 14 of ESS and 1 of AS, in the Department of Pathology of Suining Central Hospital [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Smooth muscle tissue of the uterine wall and leiomyoma tissue were also obtained if present.\u003c/p\u003e\u003cp\u003eThe expression of β-catenin was assessed by immunohistochemical method using a mouse-anti-human monoclonal antibody (MX043, MAIXIN, Fuzhou, Fujian). Tissue specimens were fixed with 10% formalin and preserved in paraffin. The paraffin-embedded blocks were sectioned continuously to a thickness of 4 \u0026micro;m and fixed on slides for immunohistochemical staining. Paraffin-embedded sections were dewaxed and then repaired using ethylenediaminetetraacetic acid (EDTA) antigen retrieval buffers. All IHC staining were performed using an automated immunostainer (VENTAN Bench Mark XT, Roche, Swiss). Human colorectal adenocarcinoma tissue was used as a positive control. The higher the expression content of β-catenin was, the greater was the distribution density and the stronger the positive result would be.\u003c/p\u003e\u003cp\u003eβ-catenin expression was evaluated using the H\u0026shy; score, which is defined as the product of the staining intensity and the percentage of positively stained cells. The scoring system for staining intensity was as follows: 0 points for no staining, 1 point for light yellow, 2 points for brown‒yellow, and 3 points for brown. The percentage of positive cells was also considered, and the scores were as follows: 0 points, positive cells 5% or less; 1 point, positive cells between 6% and 25%; 2 points, positive cells between 26% and 50%; 3 points, positive cells between 51%-75%; and 4 points, positive cells greater than 75%. The resulting total scores were categorized as negative (0 points), weakly positive (1\u0026ndash;4 points), moderately positive (5\u0026ndash;8 points), and strongly positive (9\u0026ndash;12 points). The scoring process was performed independently by two gynecologic pathologists using optical microscopy. The decision was made after discussion within the group if inconsistent.\u003c/p\u003e\u003cp\u003e\u003cb\u003eGene set enrichment analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eDifferential expressed genes (DEGs) were analyzed between β-catenin-low- and high-expression group in patients of Sweden microarray cohort using the R package DESeq2 (v1.44.0). Gene set enrichment analysis (GSEA) was then conducted using the R package clusterProfiler (v4.12.0) to explore the potential molecular mechanisms underlying the distinct gene expression [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Normalized enrichment score (NES) was calculated with gene set permutations set as 1000 times. Gene sets with |NES| \u0026gt; 1, adjusted p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, q\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered as significant enrichment.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStatistical analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe statistical analysis was performed using R (version 4.4.0). The distributions of categorical variables and continuous variables between cases and controls were performed using Pearson χ2 tests and Student\u0026rsquo;s t tests, respectively. Categorical data are presented as counts and percentages and were analyzed using the Chi-square test and Fisher\u0026rsquo;s exact test. The expression levels of β-catenin in patients were determined using the ggplot2 package.\u003c/p\u003e\u003cp\u003eBased on the cut-off value of β-catenin expression, the patients were divided into high and low-β-catenin expression groups, Kaplan-Meier analysis was used to evaluate the relationship between overall survival and β-catenin expression level and pathological subtypes in Sweden microarray dataset (GSE119043) from GEO [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] and clinical cohort from Suining hospital. Univariate and multivariate cox proportional hazard regression analyses were used to explore β-catenin expression as an independent prognostic factor of US. P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e\u003cb\u003eBaseline characteristics\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAccording to the 2023 FIGO guidelines of the uterine sarcoma, we analyzed the clinical data collected from the patients' medical records, including age, histology, clinical and pathologic stage, and adjuvant chemotherapy (CT) or radiotherapy (RT).\u003c/p\u003e\u003cp\u003eFrom an initial cohort of 56 patients, 31 patients were diagnosed with a definite pathological subtype of uterine sarcoma from Suining Central Hospital (Department of Pathology) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The baseline characteristics of these patients from the clinical (Suining) cohort were presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. All patients involved in the study were female and categorized according to pathological type into groups of adenosarcoma (AS, n\u0026thinsp;=\u0026thinsp;1), endometrial stromal sarcoma (ESS, n\u0026thinsp;=\u0026thinsp;14) (including 12 low-grade ESS (LG-ESS) and 2 high-grade ESS (HG-ESS)), and leiomyosarcoma (LMS, n\u0026thinsp;=\u0026thinsp;16). Nearly a half of them were over age 50. Most of them (n\u0026thinsp;=\u0026thinsp;20, 64.52%) were premenopausal. Surgical approaches included total hysterectomy\u0026thinsp;+\u0026thinsp;bilateral salpingo-oophorectomy (TH\u0026thinsp;+\u0026thinsp;BSO), TH\u0026thinsp;+\u0026thinsp;BSO\u0026thinsp;+\u0026thinsp;pelvic lymphadenectomy (TH\u0026thinsp;+\u0026thinsp;BSO\u0026thinsp;+\u0026thinsp;PLA), TH\u0026thinsp;+\u0026thinsp;BSO\u0026thinsp;+\u0026thinsp;PLA\u0026thinsp;+\u0026thinsp;omentectomy, and TH\u0026thinsp;+\u0026thinsp;BSO\u0026thinsp;+\u0026thinsp;PLA\u0026thinsp;+\u0026thinsp;omentectomy\u0026thinsp;+\u0026thinsp;appendectomy. A total of 48.39% (n\u0026thinsp;=\u0026thinsp;15) of all patients underwent lymphadenectomy. In addition, for adjuvant treatment, less than half of the patients (n\u0026thinsp;=\u0026thinsp;13, 41.94%) received chemotherapy (CT) with doxorubicin and ifosfamide as the primary protocol, while the rest did not. Only six patients received radiotherapy (RT), while most of patients (n\u0026thinsp;=\u0026thinsp;25, 80.65%) did not.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of 31 US patients from the Suining cohort (Line 145)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll Patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLG-ESS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHG-ESS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLMS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;31)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge at diagnosis(years), n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.389\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16(51.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(6.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6(37.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9(56.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15(48.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6(40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2(13.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7(46.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMenopausal status, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.872\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostmenopausal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11(35.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4(36.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1(9.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6(54.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePremenopausal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20(64.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8(40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1(5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10(50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSymptoms, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.118\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eColporrhagia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9(29.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4(44.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2(22.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3(33.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStomachache/bloating\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7(22.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2(28.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5(71.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbdominal mass\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10(32.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4(40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6(60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsymptomatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5(16.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2(40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2(40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor size(cm), n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.072\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10(32.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6(60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1(10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21(67.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6(28.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1(4.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14(66.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCA125(U/ml), n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.541\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14(45.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(7.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5(35.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1(7.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7(50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8(25.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2(25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1(12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5(62.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9(29.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5(55.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4(44.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFIGO stage, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.328\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅠ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22(70.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(4.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10(45.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11(50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅡ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3(9.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1(33.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1(33.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1(33.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅢ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2(6.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1(50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1(50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅣ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4(12.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4(100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSurgical approach, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.363\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTH\u0026thinsp;+\u0026thinsp;BSO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16(51.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8(50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8(50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTH\u0026thinsp;+\u0026thinsp;BSO\u0026thinsp;+\u0026thinsp;PLA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7(22.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(14.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3(42.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2(28.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1(14.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTH\u0026thinsp;+\u0026thinsp;BSO\u0026thinsp;+\u0026thinsp;PLA\u0026thinsp;+\u0026thinsp;omentectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5(16.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4(80.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTH\u0026thinsp;+\u0026thinsp;BSO\u0026thinsp;+\u0026thinsp;PLA\u0026thinsp;+\u0026thinsp;omentectomy\u0026thinsp;+\u0026thinsp;appendectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3(9.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3(100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLymphadenectomy, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15(48.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(6.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4(26.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2(13.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8(53.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16(51.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8(50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8(50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChemotherapy, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.869\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13(41.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5(38.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1(7.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7(53.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18(58.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(5.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7(38.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1(5.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9(50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRadiotherapy, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.802\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6(19.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2(33.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4(66.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25(80.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(4.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10(40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2(8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12(48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003e \u003csup\u003e1\u003c/sup\u003e TH: Total hysterectomy; TH\u0026thinsp;+\u0026thinsp;BSO: Total hysterectomy\u0026thinsp;+\u0026thinsp;bilateral salpingo-oophorectomy; PLA: Pelvic lymphadenectomy.\u003c/p\u003e \u003cp\u003e \u003cb\u003eIHC Evaluation of β-catenin\u003c/b\u003e \u003c/p\u003e \u003cp\u003eImmunohistochemistry was conducted to examine the expression of β-catenin in 31 full-face tissue sections obtained from US patients, including 24 paired samples of normal uterine smooth muscle (UNSM) and 5 paired samples of uterine leiomyoma (ULM). Positive expression of β-catenin was detected in the cell membrane and cytoplasm, appearing as light yellow, brownish yellow or dark brown particles. All specimens from US patients showed varying levels of positivity, ranging from moderate to strong.\u003c/p\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea, among 5 paired samples, the expression level of β-catenin exhibited a significant increase in the US group compared to both the UNSM and ULM groups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, both) and in the ULM group compared to the UNSM group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). Furthermore, among 24 paired samples, similar results were obtained both in the tumor tissues from US group compared to the normal tissues from UNSM group(P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eIn different pathological types, immunohistochemistry revealed a significant difference in β-catenin protein expression levels among AS, LMS, LG-ESS and HG-ESS (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). The expression of β-catenin in AS showed moderate positivity and was significantly lower than that in LMS. Furthermore, the expression of β-catenin in HG-ESS was substantially up-regulated compared with LG-ESS, although there were only two patients. Obviously, the findings indicated that LMS and HG-ESS patients exhibited the higher levels of β-catenin expression when compared with other types. However, the box plot showed there was no significance in β-catenin expression among AS, LMS, LG-ESS and HG-ESS (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb, P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e\u003cb\u003eSurvival analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eSurvival analysis indicated that with high β-catenin expression levels had no significance with OS (HR, 2.046; 95%CI: 0.4299\u0026ndash;9.737; P\u0026thinsp;=\u0026thinsp;0.36; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea) and PFS (HR, 0.5296; 95%CI: 0.1544\u0026ndash;1.817; P\u0026thinsp;=\u0026thinsp;0.30; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb) in Suining cohort. The median OS in the high- or low-β-catenin expression group were not reached (NR). The median PFS in low-β-catenin group was not reached (NR), indicating a longer but not statistically significant survival compared to the median PFS of high expression group (61.73 months VS 34.75 months). The similar results of OS were obtained in 50 UUS patients from the Sweden microarray cohort (HR, 0.5724; 95%CI: 0.2688\u0026ndash;1.219; P\u0026thinsp;=\u0026thinsp;0.14; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec), while low-β-catenin expression group also showed a longer but no statistical significance median OS compared to the high expression group (56.17 months VS 9.60 months).\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003e \u003cb\u003eUnivariate and multivariate cox regression analysis\u003c/b\u003e \u003c/p\u003e \u003cp\u003eUnivariate and multivariate cox proportional hazard regression analyses were carried out with US patients from the Sweden microarray cohort. The univariate analysis indicated that copy number variation (CNV) group (HR\u0026thinsp;=\u0026thinsp;2.04; 95% CI: 1.05\u0026ndash;3.96; P\u0026thinsp;=\u0026thinsp;0.034), hormone receptor expression (HR, 0.21; 95%CI: 0.09\u0026ndash;0.48; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), mitotic index group (HR, 2.33; 95% CI: 1.21\u0026ndash;4.50; P\u0026thinsp;=\u0026thinsp;0.012) and nuclear atypia (HR, 1.96; 95% CI: 1.01\u0026ndash;3.80; P\u0026thinsp;=\u0026thinsp;0.046) were significantly associated with OS in US patients. Multivariate analysis showed hormone receptor expression (HR, 0.24; 95% CI: 0.10\u0026ndash;0.60; P\u0026thinsp;=\u0026thinsp;0.002), and mitotic index group (HR, 2.70; 95% CI: 1.21\u0026ndash;6.05; P\u0026thinsp;=\u0026thinsp;0.016) still remained the same results (Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). However, we noted no substantial correlation between CTNNB1 expression and OS (HR, 1.75; 95% CI: 0.82\u0026ndash;3.72; P\u0026thinsp;=\u0026thinsp;0.148;). Additional clinical indicators, including cell density, displayed no relationship with OS (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The findings were presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate cox analysis of OS in US patients from the Sweden microarray cohort (Line 206)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFeatures\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCell density (High vs. Low)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.51\u0026ndash;1.80\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.891\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCNV group (High vs. Low)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e2.04\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1.05\u0026ndash;3.96\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.034\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHormone receptor expression (Positive vs. Negative)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.21\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.09\u0026ndash;0.48\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMitotic index group (High vs. Low)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e2.33\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1.21\u0026ndash;4.50\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.012\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNuclear atypia (Pleomorphic vs. Uniform)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e1.96\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1.01\u0026ndash;3.80\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.046\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRNA group (Developmental vs. Others)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.70\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.37\u0026ndash;1.32\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.270\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCTNNB1 expression (High vs. Low)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e1.75\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.82\u0026ndash;3.72\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.148\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eFurthermore, we conducted univariate and multivariate cox proportional hazard regression analyses of OS and PFS in US patients from the clinical cohort. Our analysis demonstrated that tumor type, lymphadenectomy, family history of malignancy and tumor recurrence remained significant predictors of OS, while only tumor stage and tumor recurrence were associated with PFS (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Univariate analyses demonstrated that only tumor recurrence (HR, 44.22; 95% CI: 5.39-363.12; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) was significantly associated with OS and PFS in US patients. Nevertheless, the results indicated an absent relationship between β-catenin expression and OS (HR, 1.53; 95% CI: 0.40\u0026ndash;5.93; P\u0026thinsp;=\u0026thinsp;0.383) or PFS (HR, 2.24; 95% CI: 0.46\u0026ndash;10.82; P\u0026thinsp;=\u0026thinsp;0.317) in US patients, consistent with prior study from the Sweden cohort. Moreover, other clinical variables did not influence OS and PFS (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05, Supplementary Table S2-S3).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate cox analysis of PFS in US patients from the Suining cohort (Line 212)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eClinicopathological features\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (\u0026le;\u0026thinsp;50 vs. \u0026gt;50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.43\u0026ndash;5.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.490\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor stage (I/II vs. III/IV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.97\u0026ndash;29.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMenopausal status (Postmenopausal\u003c/p\u003e \u003cp\u003evs. Premenopausal)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.10\u0026ndash;2.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.384\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size (\u0026le;\u0026thinsp;5 vs. \u0026gt;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.44\u0026ndash;10.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.348\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA125 (\u0026lt;35 vs. \u0026gt;35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.78\u0026ndash;5.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.147\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphadenectomy (Yes vs. No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.88\u0026ndash;20.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.073\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily history of malignancy (Yes vs. No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.96\u0026ndash;88.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.055\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor recurrence (Yes vs. No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e44.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.39-363.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdjuvant chemotherapy (Yes vs. No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.50\u0026ndash;7.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.344\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdjuvant radiotherapy (Yes vs. No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.23\u0026ndash;5.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.886\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eβ-catenin expression (High vs. Low)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.46\u0026ndash;10.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.317\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate cox analysis of OS in US patients from the Suining cohort (Line 212)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eClinicopathological features\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (\u0026le;\u0026thinsp;50 vs. \u0026gt;50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.79\u0026ndash;11.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.107\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor stage (I/II vs. III/IV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.99\u0026ndash;12.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMenopausal status (Postmenopausal\u003c/p\u003e \u003cp\u003evs. Premenopausal)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.33\u0026ndash;4.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.798\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size (\u0026le;\u0026thinsp;5 vs. \u0026gt;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.37\u0026ndash;5.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.610\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA125 (\u0026lt;35 vs. \u0026gt;35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.94\u0026ndash;5.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.068\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor type (AS\u0026thinsp;+\u0026thinsp;LG-ESS vs. LMS\u0026thinsp;+\u0026thinsp;HG-ESS)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.12\u0026ndash;71.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphadenectomy (Yes vs. No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.05\u0026ndash;23.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.043\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily history of malignancy (Yes vs. No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.28-156.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.031\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor recurrence (Yes vs. No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.09\u0026ndash;50.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdjuvant chemotherapy (Yes vs. No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.46\u0026ndash;5.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.453\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdjuvant radiotherapy (Yes vs. No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.06\u0026ndash;3.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.480\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eβ-catenin expression (High vs. Low)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.40\u0026ndash;5.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.538\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003e \u003cb\u003eGSEA to get first hints about the specific pathways involved in β-catenin\u003c/b\u003e \u003c/p\u003e \u003cp\u003eBased on the potential prognostic significance of β-catenin expression level in uterine sarcoma, we investigated the underlying biological mechanisms. Differential expressed genes (DEGs) were analyzed between β-catenin high- and low-expression group in patients from Sweden cohort, and gene set enrichment analysis (GSEA) was then performed to characterize the specific pathways that involved in the β-catenin expression. The positively enriched gene sets in the β-catenin-high expression group included AMP-activated protein kinase (AMPK) signaling pathway, endometrial cancer, mito-gen-activated protein kinase (MAPK) signaling pathway, protein 53 (p53) signaling pathway, phosphatidylinositol-3-kinase/protein kinase B (PI3K-Akt) signaling pathway, rat sarcoma (Ras) signaling pathway, tumor necrosis factor (TNF) signaling pathway, Wnt signaling pathway, and transcriptional misregulation in cancer. On the other hand, ascorbate and aldarate metabolism, cytokine-cytokine receptor interaction, pentose and glucuronate interconventions, retinol metabolism, steriod hormone biosynthesis, taurine and hypotaurine metabolism, were negatively enriched in the β-catenin-high-expression group (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Supplementary Table S4).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eUterine sarcomas are rare and aggressive gynecologic malignancies, characterized by a relatively high recurrence rate. The prognosis of uterine sarcoma remains poor, with a mortality rate of up to 30% due to its highly aggressive nature [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. There are few effective prognostic biomarkers or models for improving the clinical outcomes of US patients. In general, US patients always diagnosed after menopause [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Interestingly, a significant number of women remained in the premenopausal phase in our study. This finding hints at an evolving trend towards rejuvenation worth monitoring.\u003c/p\u003e \u003cp\u003ePrevious research proposed that specific fusion proteins in LG-ESS contribute to overexpression of Wnt ligands with subsequent activation of Wnt signaling pathway and formation of an active β-catenin/Lef1 transcriptional complex [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In this study, we confirmed that the expression level of β-catenin significantly upregulated in the US group compared to both the UNSM and ULM groups. Furthermore, immunohistochemistry exhibited a significant difference in β-catenin expression levels in four pathological subtypes. LMS and HG-ESS exhibited higher levels of β-catenin expression compared with AS or LG-ESS, but no statistically significant difference was displayed. Survival analyses showed that no significance between β-catenin expression levels and OS or PFS. The late endpoint events of patients (reaching beyond follow-up cut-off), may affect the results. As indicated by the above results, β-catenin was closely correlated with uterine sarcoma.\u003c/p\u003e \u003cp\u003eBased on our study, we discovered only tumor recurrence was significantly correlated with poor survival. Tumor type, lymphadenectomy, family history of malignancy and tumor recurrence remained significant predictors of OS, while only tumor stage and tumor recurrence had prognostic significance for PFS. We respectfully diverged from Wang et al.'s claim on the correlation between tumor size and survival (OS and PFS) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Other clinical variables, such as age, menopausal status, CA125, adjuvant chemotherapy, and adjuvant radiotherapy, did not influence survival (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Despite lacking survival correlations, elevated circulating CA125 levels were noted in nearly a half of patients. Focusing on these patients may prompt potential benefits for diagnosis.\u003c/p\u003e \u003cp\u003eCurrently, there was no standard therapeutic options for uterine sarcoma, with varying perspectives on surgical method. The cornerstone of the approach to US is hysterectomy and bilateral salpingo-oophorectomy (BSO) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. It was reported that incomplete surgery was associated with poor prognosis [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Our research suggested that lymphadenectomy influenced OS in uterine sarcoma patients, aligning well with Machida's work [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Additionally, we found that adjuvant chemotherapy or radiotherapy was no significance with survival, consistent with prior research results [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Whether radiotherapy or chemotherapy should be given after surgery is still debated.\u003c/p\u003e \u003cp\u003eIn this study, we first explored β-catenin expression level and its potential role as an effective predictive biomarker for prognosis prediction of uterine sarcoma. We found that β-catenin was highly expressed in US, compared with UNSM and ULM, while survival analyses and cox regression analyses in the Sweden and Suining cohorts showed that there was no significant correlation between β-catenin expression level and the prognosis of US patients. These findings suggested that β-catenin was highly expressed in uterine sarcoma and would be promising as a novel potential biomarker for the diagnosis and prognosis of uterine sarcoma.\u003c/p\u003e \u003cp\u003eWnt/β-catenin aberrant activation is linked with increased cancer occurrence, tumor progression, adverse prognosis development, and cancer-related mortality risk in human cancers. Altered β-catenin is thought to drive tumorigenesis in multiple cancers [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], notably colorectal cancer [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] and endometrial carcinoma (EC) [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Somatic mutation in coded gene hotspots or mutational inactivation of Adenomatous polyposis coli (APC) are two main mechanisms existed in endometrial carcinoma for increasing β-catenin levels. Tumors with β-catenin coded gene hotspot mutations exhibited higher Wnt signaling pathway activity, characterized by increased expression of the key protein β-catenin within the pathway. β-catenin, APC, Axin (axin inhibitor), CK-1α protein (casein kinase 1α protein) and GSK-3β protein (glycogen synthase kinase 3β protein) formed the destruction complex that captured β-catenin by phosphorylating CK1 and GSK3, thus activating the process of β-catenin degradation. The mutational inactivation of APC leaded to the accumulation of β-catenin [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. In our study, the positive enrichment of Wnt signaling pathway in the β-catenin high-expression group supported that β-catenin would be a satisfactory tool to predict prognosis in uterine sarcoma patients.\u003c/p\u003e \u003cp\u003eSeveral tumor progression related gene sets, including Wnt, TNF, AMPK, MAPK, p53, PI3K-Akt, Ras signaling pathway, endometrial cancer, and transcriptional misregulation in cancer, were the potential predominant molecular pathways implicated in the uterine sarcoma development. For example, YWHAE-NUTM2 regulated cyclin D1 expression and cell proliferation by dysregulating RAF/MEK/MAPK and Hippo/YAP-TAZ signaling pathways in HG-ESS [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Intriguingly, autophagy inhibitor 3-Methyladenine (3-MA) potentiated the antitumor efficacy of apatinib in uterine sarcoma by stimulating PI3K/Akt/mTOR pathway [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. On the other hand, the results suggested that several negatively enriched pathways in β-catenin low-expression group mainly involved in metabolism and hormone biosynthesis. Taurine not only inhibited cancer cell proliferation but also induced apoptosis in certain cancers by differential regulating proapoptotic and antiapoptotic proteins [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Taurine and hypotaurine metabolism pathway was continually disturbed during the progression of gastric carcinogenesis (GCG), potentially due to abnormal energy supply for tumor cell proliferation and growth [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. In endometrial cancer (EC), Kaempferol affected multiple estrogen metabolism pathways by regulating HSD17B1 and HSD17B1-associated genes, which were involved in steroid hormone biosynthesis and regulation of hormone levels [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The above pathways were the potential crucial mechanisms to explore the role of β-catenin in uterine sarcoma genesis and progression.\u003c/p\u003e \u003cp\u003eCertainly, our study has limitation. Given a total of only 50 patients for Sweden microarray cohort and 31 patients for Suining cohort, it is worth noting that the sample size might limit our ability to draw significant conclusions. Going forward, we plan to keep long-term follow-up for the patients and further explore the mechanism of β-catenin in the development of uterine sarcoma.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eβ-catenin was highly expressed in uterine sarcoma and would be promising as a novel potential biomarker for the diagnosis and prognosis of uterine sarcoma.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eSupplementary Materials:\u0026nbsp;\u003c/strong\u003eThe following supporting information can be downloaded at: www.mdpi.com/xxx/s1, Table S1: Multivariate cox analysis of OS in US patients from the Sweden microarray cohort; Table S2: Multivariate cox analysis of PFS in US patients from the Suining cohort; Table S3: Multivariate cox analysis of OS in US patients from the Suining cohort.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e Conceptualization, Jian-Guo Zhou; Data curation, Yunjia Wang, Ling Yang and Yue Huang; Formal analysis, Min-Jun Chen and Chi Zhang; Funding acquisition, Hu Ma and Jian-Guo Zhou; Methodology, Jian-Guo Zhou; Project administration, Jian-Guo Zhou; Resources, Jian-Guo Zhou; Supervision, Jian-Guo Zhou; Visualization, Ying Cai; Writing \u0026ndash; original draft, Ying Cai; Writing \u0026ndash; review \u0026amp; editing, Su-Han Jin, Benjamin Frey, Udo Gaipl, Hu Ma and Jian-Guo Zhou. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This research was funded by the National Natural Science Foundation of China, Grant No. 82060475; Chunhui program of the Chinese Ministry of Education, Grant No. HZKY20220231; the Natural Science Foundation of Guizhou Province, Grant No. ZK2022-YB632; Youth Talent Project of Guizhou Provincial Department of Education, Grant No. QJJ2022-224; China Lung Cancer Immunotherapy Research Project, Excellent Young Talent Cultivation Project of Zunyi City, Zunshi Kehe HZ (2023) 142; Future Science and Technology Elite Talent Cultivation Project of Zunyi Medical University, ZYSE-2023-02; Collaborative Innovation Center of Chinese Ministry of Education, Grant No. 2020-39.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement:\u0026nbsp;\u003c/strong\u003eThe study was conducted in accordance with the Declaration of Helsinki, and approved by the Review Board of Suining Central Hospital (No. LLSLH20220051) and the Ethics Committee of Zunyi Medical University (No. 2020-1-013). Informed consent was obtained from each participant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement:\u003c/strong\u003e Informed consent was obtained from all subjects involved in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u0026nbsp;\u003c/strong\u003eThe data for uterine sarcoma in GSE119043 are available at the Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) portal. Analysis tools are listed in Methods. The data for Suining cohort presented in this article are not readily available because the data are part of an ongoing study, due to necessary secrecy. Requests to access the datasets should be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e The authors declare no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eD\u0026apos;Angelo E, Prat J: \u003cstrong\u003eUterine sarcomas: a review.\u003c/strong\u003e \u003cem\u003eGynecol Oncol\u0026nbsp;\u003c/em\u003e2010, \u003cstrong\u003e116:\u003c/strong\u003e131-139.\u003c/li\u003e\n \u003cli\u003eMatsuo K, Takazawa Y, Ross MS, Elishaev E, Podzielinski I, Yunokawa M, Sheridan TB, Bush SH, Klobocista MM, Blake EA, et al: \u003cstrong\u003eSignificance of histologic pattern of carcinoma and sarcoma components on survival outcomes of uterine carcinosarcoma.\u003c/strong\u003e \u003cem\u003eAnn Oncol\u0026nbsp;\u003c/em\u003e2016, \u003cstrong\u003e27:\u003c/strong\u003e1257-1266.\u003c/li\u003e\n \u003cli\u003eRoberts ME, Aynardi JT, Chu CS: 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Pharmacol\u0026nbsp;\u003c/em\u003e2021, \u003cstrong\u003e88:\u003c/strong\u003e323-334.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"β-catenin, Prognosis, Uterine sarcoma, Biomarker","lastPublishedDoi":"10.21203/rs.3.rs-4740736/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4740736/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eUterine sarcoma (US) is an extremely rare and aggressive gynecologic malignancy with a poor overall survival (OS). The early screening and diagnosis of uterine sarcoma is still challenging, while efficient prognostic biomarker is currently lacking. In this study, we evaluated the expression of β-catenin in different US subtypes and the relationship between survival and clinicopathological characteristics by comparative analyses, then explored potential molecular mechanisms.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe evaluated the expression of β-catenin in different US subtypes and the relationship between survival and clinicopathological characteristics by comparative analyses. Utilizing a Sweden microarray dataset (GSE119043, n=50) and a Suining clinical cohort (n=31), we analyzed β-catenin expression profiles and corresponding clinicopathological characteristics. To assess the expression level of β-catenin in US subtypes, we conducted immunohistochemistry (IHC). Survival analysis was used to assess the relationship between β-catenin expression and prognosis in US patients. Gene set enrichment analysis (GSEA) was performed to characterize the specific pathways involved in the β-catenin expression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Immunohistochemistry indicated that the expression level of β-catenin significantly upregulated in the uterine sarcoma (US) group compared to both the normal uterine smooth muscle (UNSM) and uterine leiomyoma (ULM) groups (P\u0026lt;0.05). IHC also exhibited a significant difference in β-catenin expression levels in four pathological subtypes. Leiomyosarcoma (LMS) and high-grade endometrial stromal sarcoma (HG-ESS) suggested higher levels of β-catenin expression compared with adenosarcoma (AS) or low-grade endometrial stromal sarcoma (LG-ESS), but no statistically significant difference was found in box plot. Survival analysis showed that no significance between β-catenin expression levels and survival. Only tumor recurrence was significantly correlated with poor survival. Tumor type, lymphadenectomy, family history of malignancy and tumor recurrence remained significant predictors of overall survival (OS), while only tumor stage and tumor recurrence had prognostic significance for progression-free survival (PFS). Age, tumor size, menopausal status, CA125, adjuvant chemotherapy, and adjuvant radiotherapy, were not associated with survival (P\u0026gt;0.05). GSEA indicated that transcriptional misregulation in cancer, Wnt, AMPK, MAPK, PI3K, p53, Ras, and TNF signaling pathway were positively enriched in β-catenin high-expression group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e β-catenin was highly expressed in uterine sarcoma and promising as a novel potential biomarker for diagnosis and prognosis.\u003c/p\u003e","manuscriptTitle":"β-catenin is a potential prognostic biomarker in uterine sarcoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-11 12:40:53","doi":"10.21203/rs.3.rs-4740736/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1ef1bc77-548a-4d30-8466-b9a9a284fb44","owner":[],"postedDate":"August 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-24T00:38:15+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-11 12:40:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4740736","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4740736","identity":"rs-4740736","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}