Prognosis Of Endometrial Cancer Research Articles

Identification of inflammatory-related gene signatures to predict prognosis of endometrial carcinoma

Little is known about the prognostic risk factors of endometrial cancer. Therefore, finding effective prognostic factors of endometrial cancer is the vital for clinical theranostic. In this study, we constructed an inflammatory-related risk assessment model based on TCGA database to predict prognosis of endometrial cancer. We screened inflammatory genes by differential expression and prognostic correlation, and constructed a prognostic model using LASSO regression analysis. We fully utilized bioinformatics tools, including ROC curve, Kaplan–Meier analysis, univariate and multivariate Cox regression analysis and in vitro experiments to verify the accuracy of the prognostic model. Finally, we further analyzed the characteristics of tumor microenvironment and drug sensitivity of these inflammatory genes. The higher the score of the endometrial cancer risk model we constructed, the worse the prognosis, which can effectively provide decision-making help for clinical endometrial diagnosis and treatment.

CRABP2 – A novel biomarker for high-risk endometrial cancer

ObjectiveInvestigate the clinical and functional implications of elevated CRABP2 expression in endometrial cancer (EC) patients. MethodsPatients were stratified into high and low CRABP2 expression groups using a decision tree classifier. Univariate and multivariate statistical analyses determined the prognostic and clinicopathological consequences of increased CRABP2 expression. A CRABP2 gene signature was generated using differential expression analysis, and analyzed using network-based approaches. The findings were validated in The Clinical Proteomic Tumor Analysis Consortium (CPTAC), a newly generated cohort of 120 endometrial tissues, and The Cancer Dependency Map (DepMap). Results60 (11%) patients in TCGA had high CRABP2 expression, whilst 468 (89%) had low expression. High expression was associated with serous EC, reduced overall survival, advanced stage and grade. Downstream retinoic acid receptors (RARG and RARA) were correlated with CRABP2 expression and were associated with worse prognosis in serous EC. The CRABP2 gene signature was enriched for Polycomb target gene sets, and was regulated by ELP3 and BMP7. BMP7 expression was increased in the CRABP2-high group, was associated with worse prognosis, and CRISPR-Cas9 screens revealed correlations in its cell-fitness score with CRABP2 following gene knockout. The opposite was true for ELP3, suggesting opposing effects from both master regulators. ConclusionsCRABP2 expression is associated with poor prognosis and advanced EC. The expression of RARA and RARG correlates with CRABP2 and are associated with worse prognosis in advanced histological subtypes. Polycomb target gene sets and two master regulators, ELP3 and BMP7, were identified as functionally relevant mechanisms driving aberrant CRABP2 expression.

Reclassification of endometrial cancer and identification of key genes based on neural-related genes.

Endometrial cancer (EC) is the most common gynecologic malignancy, and its incidence has been increasing every year. Nerve signaling is part of the tumor microenvironment and plays an active role in tumor progression and invasion. However, the relationship between the expression of neural-related genes (NRGs) and prognosis in endometrial cancer remains unknown. In this study, we obtained RNA sequencing data of EC from The Cancer Genome Atlas (TCGA). Endometrial cancer was classified into two subtypes based on the expression of neural-associated genes (NRGs), with statistical differences in clinical stage, pathological grading, and prognosis. A prognostic prediction model was established by LASSO-Cox analysis, and the results showed that high expression of NRGs was associated with poor survival prognosis. Further, CHRM2, GRIN1, L1CAM, and SEMA4F were found to be significantly associated with clinical stage, immune infiltration, immune response, and important signaling pathways in endometrial cancer. The reclassification of endometrial cancer based on NRG expression would be beneficial for future clinical practice. The genes CHRM2, GRIN1, L1CAM, and SEMA4F might serve as potential biomarkers of EC prognosis.

Claudin‑9 is a novel prognostic biomarker for endometrial cancer.

The tight-junction protein claudin-9 (CLDN9) is barely distributed in normal adult tissues but is ectopically expressed in various cancer types. Although multiple databases indicated upregulation of CLDN9 in endometrial cancers at the mRNA level, its protein expression and biological roles remain obscure. In the present study, the prognostic significance of CLDN9 expression in endometrial cancer was evaluated by immunohistochemical staining and semi-quantification using formalin-fixed paraffin-embedded specimens obtained from 248 endometrial carcinoma cases. A total of 43 cases (17.3%) had high CLDN9 expression, whereas 205 cases (82.7%) exhibited low CLDN9 expression. The 5-year disease-specific survival rates in the high and low CLDN9 expression groups were 62.8 and 87.8% (P<0.001), respectively. In addition, multivariate analysis revealed that high CLDN9 expression was an independent prognostic factor (hazard ratio, 4.99; 95% CI, 1.96-12.70; P<0.001). Furthermore, CLDN9 expression was significantly correlated with the expression of CLDN6 (P<0.001), which is the closest CLDN member to CLDN9 and a poor prognostic factor for endometrial carcinoma. The 5-year disease-specific survival rate of cases with CLDN6-high/CLDN9-high, CLDN6-high/CLDN9-low and CLDN6-low/CLDN9-high status was 30.0, 37.5 and 72.7%, respectively, whereas that of CLDN6-low/CLDN9-low was 89.8% (P=0.004). In conclusion, aberrant CLDN9 expression is a predictor of poor prognosis for endometrial cancer and may be utilized in combination with CLDN6 to achieve higher sensitivity.

FBXL16 Promotes Endometrial Progesterone Resistance via PP2AB55α /Cyclin D1 Axis in Ishikawa.

Background F-box proteins are essential components of the E3 ubiquitin ligases which are involved in the regulation of almost all life activities such as cell cycle, proliferation, and apoptosis, which have become an important research and drug target. However, there are few studies on F-box and leucine-rich repeat protein 16 (FBXL16) in endometrial carcinoma. Methods Clinical samples were collected for determining the correlation between FBXL16 and endometrial carcinoma. Cells were screened and established with Ishikawa cells which proved the fundamental role of FBXL16 in regulating cell proliferation and cell cycle. The MPA-resistant endometrial carcinoma cell line Ishikawa/MPA was established. FBXL16, PP2AB55α, and cyclin D1 were analyzed separately in MPA sensitive and resistant Ishikawa cells in vitro and in vivo. Results The high expression of FBXL16 was positively correlated with MPA resistance and poor prognosis of endometrial cancer. MPA tolerance of endometrial cancer cells was inhibited by knockdown of FBXL16 in DNA content assessment, CCK-8, and colony formation. It was confirmed that FBXL16 inhibited the activity of substrate PP2AB55α by binding to PP2A, reduced the phosphorylation level at Thr308 site of AKT1, inhibited the expression of GSK-3β, and thus led to a significant decrease in the phosphorylation level of cyclin D1, which prevented the ubiquitination recognition and degradation of cyclin D1. Conclusion In our experiments, FBXL16 binds PP2A to promote the dephosphorylation of Thr286 site of cyclin D1 via AKT1/GSK3β/cyclin D1 pathway, which is required for resisting the ubiquitination degradation and enhances the MPA resistance of Ishikawa.

Prognostic value of angiogenic markers of endometrial cancer (literature review)

Endometrial cancer is the most common cancer of the female reproductive organs. The purpose of the study was to summarize the available data on the role of angiogenic markers in the development, progression and prognosis of endometrial cancer. Material and methods. A literature search was conducted using Medline and Pubmed databases using the key words: “endometrial cancer”, “endometrial hyperplasia” and others. 56 publications were selected to write this review. Results. Currently, there is a variety of different data on the relationship between molecular markers of angiogenesis in endometrial cancer and the prognosis of endometrial cancer. The article summarizes the results of the most recent studies devoted to the study of angiogenic markers of endometrial cancer, as well as the characteristics of the microvasculature. We focused on the prognostic and diagnostic values of these morphological and molecular changes. particular attention was paid to the inactivation of the oncosuppressive protein PTEN, an inhibitor of the PI3K/Akt/mTOR-signaling pathway, which plays an important role in the pathogenesis and prognosis of endometrial cancer. Conclusion. Many of the markers of angiogenesis can be used to assess the development and prognosis of endometrial cancer. However, conflicting research results with respect to some markers require further study, their validation, and subsequent implementation into practice.

Targeting immunometabolism mediated by the IDO1 Pathway: A new mechanism of immune resistance in endometrial cancer.

Immunotherapy is acquiring a primary role in treating endometrial cancer (EC) with a relevant benefit for many patients. Regardless, patients progressing during immunotherapy or those who are resistant represent an unmet need. The mechanisms of immune resistance and escape need to be better investigated. Here, we review the major mechanisms of immune escape activated by the indolamine 2,3-dioxygenase 1 (IDO1) pathway in EC and focus on potential therapeutic strategies based on IDO1 signaling pathway control. IDO1 catalyzes the first rate-limiting step of the so-called “kynurenine (Kyn) pathway”, which converts the essential amino acid l-tryptophan into the immunosuppressive metabolite l-kynurenine. Functionally, IDO1 has played a pivotal role in cancer immune escape by catalyzing the initial step of the Kyn pathway. The overexpression of IDO1 is also associated with poor prognosis in EC. These findings can lead to advantages in immunotherapy-based approaches as a rationale for overcoming the immune escape. Indeed, besides immune checkpoints, other mechanisms, including the IDO enzymes, contribute to the EC progression due to the immunosuppression induced by the tumor milieu. On the other hand, the IDO1 enzyme has recently emerged as both a promising therapeutic target and an unfavorable prognostic biomarker. This evidence provides the basis for translational strategies of immune combination, whereas IDO1 expression would serve as a potential prognostic biomarker in metastatic EC.

552P The prognostic evaluation of lymph-vascular space invasion to patients with endometrioid cancer and non-endometrioid cancer

The impact of lymph-vascular space invasion (LVSI) on the prognosis of endometrial cancer (EC) patients remains controversial and lacks support from large sample size studies. Very few have examined whether LVSI is related to prognosis of non-endometrioid cancer patients. Our goal was to determine the impact of LVSI on the clinical prognosis of patients with endometrioid and non-endometrioid cancer respectively. This multicenter retrospective cohort study used the Chinese Endometrial Carcinoma Consortium database to identify 3715 women with endometrioid and non-endometrioid cancer who underwent initial surgical treatment between January 1, 2010 and December 31, 2019 and without other malignancies. The median (interquartile range) duration of follow-up was 39 (22-63) months. Patients were stratified based on histopathologic types and LVSI status. A propensity score matching (PSM) algorithm was used to balance the clinical characteristics (ratio 1:1). The impact of LVSI on the prognosis was examined using Kaplan-Meier analysis. univariate and multivariate Cox proportional hazards regression analyses were performed to identify independent high-risk factors of DFS and OS. The end points were disease-free survival (DFS) and overall survival (OS) and were assessed in the endometrioid and non-endometrioid cancer population. Among the 3715 women, LVSI was found in 346 (9.31%) cases. In the after PSM cohorts, LVSI significantly decreased the DFS (P=0.005), but not OS (P=0.66) of endometrioid cancer patients. For patients with non-endometrioid cancer, there was no statistical difference in DFS (P=0.54) or OS (P=0.51). In multivariate Cox proportional hazards regression, LVSI was an independent risk factor of DFS (hazard ratio [HR], 2.62 [95% CI, 1.35-5.10]; P=0.005) and not OS (HR, 1.24 [95% CI, 0.49-3.13]; P=0.66) for endometrioid cancer patients. LVSI was not a prognostic factor of neither DFS (HR, 1.28 [95% CI, 0.58-2.81]; P=0.54) or OS (HR, 1.33 [95% CI, 0.55-3.13]; P=0.52) for non-endometrioid cancer patients. The presence of LVSI was associated with decreased DFS of endometrioid cancer patients, and had no influence on the prognosis of non-endometrioid cancer patients.

551P Genomic DNA analysis of cervical smear samples of endometrial cancer with next-generation sequencing: A prospective study

Tumor marker, CT, MRI, and cervical smear were conventional methods for early diagnosis and predict prognosis in endometrial cancer, but they still had limitations. Cervical smear samples, which are easy to obtain, and reflect the tumor environment, are sequenced in this study.

Surgical treatment in older patients with endometrial cancer: A retrospective study

IntroductionOlder patients (OP) diagnosed with endometrial cancer (EC) are less likely to receive an optimal surgical treatment compared with non-older patients (NOP). This undertreatment along with the presence of more aggressive tumours at diagnosis can explain the worse prognosis of EC in OP. There is limited evidence comparing perioperative outcomes between OP and NOP, and the benefit of applying complex procedures to OP is still controversial. The primary objective of the study was to compare intraoperative and postoperative complications between NOP and OP with EC that underwent primary surgery. Secondary objectives were to compare surgical management and survival rates. MethodsThis is a retrospective single-centre observational study including women undergoing surgery for EC between 2010 and 2019. Patients were classified according to age as NOP (younger than 75 years) or OP (75 years or older). Basal characteristics and surgical outcomes of groups were compared using Chi-square, Fisher's exact tests, student T-tests or Mann Whitney tests. Kaplan Meier analysis was used to evaluate survival. ResultsIn total 281 patients underwent primary surgery for EC between 2010 and 2019 in our centre. At diagnosis, 184 patients were younger than 75 years while 97 were 75 and older. No differences were found in disease characteristics. Most of our patients (83,3%) underwent laparoscopic surgery. Pelvic (58,2% vs. 37,1%, p = 0,001) and para-aortic (46,7% vs. 23,7%, p < 0,001) lymphadenectomies were performed more frequently in NOP compared with OP. Rates of intra-operative (6,5% vs. 12,4%, p = 0,116) and post-operative (13,0% vs. 20,6%, p = 0,120) complications were not statistically different between NOP and OP, and neither was the rate of severe complications according to Clavien-Dindo classification (5,4% vs. 8,2% of complications grade III-V respectively, p = 0,387). The 5-year disease-specific survival (DSS) rate tended to be lower in the OP than in the NOP (74,8% vs. 82,5%, p = 0,071). Considering only patients in whom complete surgical staging was performed, OP presented similar DSS to NOP, with comparable complication rate. ConclusionsOP do not present a significantly higher rate of perioperative complications compared to NOP. However, they underwent fewer lymphadenectomies and tended to present poorer DSS. Further studies are needed to standardize the surgical management of these patients.

Hypomethylated gene RAC3 induces cell proliferation and invasion by increasing FASN expression in endometrial cancer.

Endometrial cancer (EC) is one of the most prevalent gynecological cancers with a 5-year survival rate of 20-60%. Feasible prognostic molecular biomarkers of EC are necessary for accurate prediction of EC prognosis. RAC3 is a member of the Rho GTPases. Public databases including Gene Expression Profiling Interactive Analysis (GEPIA2), Tumor Immune Estimation Resource (TIMER), LinkedOmics, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), TISIDB and cBioPortal were employed to analyze the differential expression, clinicopathologic characteristics, functional networks, immune cell infiltrates and genetic alteration of RAC3 in EC patients. RAC3 expression was elevated in EC patients analyzed by TIMER and GEPIA. Overexpression of RAC3 was obviously correlated with clinical stage, histological type, histological grade and DNA hypomethylation. Patients with high RAC3 expression displayed poor overall survival. Functional enrichment analysis showed that RAC3 was involved in translational initiation, DNA replication and mRNA processing. RAC3 expression was negatively associated with infiltrating levels of B cells, CD8+T cells, macrophages and dendritic cells in EC. Experiments in vitro showed that RAC3 was upregulated in EC tissues and cell lines, and RAC3 induced cell proliferation and invasion by increasing fatty acid synthase (FASN) expression. High expression of RAC3iscorrelated with poor prognosis and low infiltration of immune cells in EC. RAC3 promotes cell proliferation and invasion via FASN. These results demonstrate thatRAC3 functions as an EC oncogene and reveal its underlying mechanism in EC progression, suggesting that RAC3 may serve as a potential therapeutic target in EC.

Microsatellite instability and oncological outcomes in Thai patients with endometrial cancer

Here, we determined the frequency of microsatellite instability (MSI) and the impact of MSI-high (MSI-H) on clinical outcomes of Thai patients with endometrial cancer (EC). Tissue samples of 110 Thai patients with EC, who had undergone surgical staging, were tested for mismatch repair (MMR) gene deficiency, and the patients were grouped into MSI-H and MSI-stable (MSI-S) groups; 24.5% had MSI-H. Unlike MSI-S group patients, MSI-H group patients had synchronous and metachronous cancer. They showed better 3-year disease-free survival (DFS) than those in the MSI-S group (p=.182; 92.3% vs. 82.6%). The 3-year overall survival was 96.2% in MSI-H and 86.4% in MSI-S groups (p=.163). Multivariate analyses showed lower uterine involvement (p=.004), myometrial invasion ≥50% (p=.032), lymphovascular space invasion (p<.001) and MSI-S (p=.006) as prognostic factors for DFS. Our study showed that the prevalence of MMR gene deficiency in Thai patients with EC is common and associated with better outcomes. Impact Statement What is already known on this subject? Microsatellite instability (MSI) occurs in approximately 20–40% of endometrial cancer (EC) cases. MSI analysis in EC can identify patients at higher risk of hereditary nonpolyposis colorectal cancer and those having prognostic factors. Additionally, it is predictive of immune checkpoint inhibitor treatment. However, current evidence shows a correlation between clinicopathological characteristics and EC prognosis. Studies on EC and MSI status effect on survival outcome have yielded inconsistent results regarding the pathological significance of MSI in such malignancies. What do the results of this study add? The prevalence of mismatch repair (MMR) gene deficiency in Thai patients with EC is common (24.5%) and associated with better outcomes. What are the implications of these findings for clinical practice and/or further research? This study highlights the prevalence and impact of MSI on oncological outcomes in patients with EC in a low-incidence country. Future studies should focus on the detection of germline mutation to understand the accurate prevalence of Lynch syndrome in Thai patients with EC.

Combining molecular subtype and traditional histo-pathologic tumor classifications to predict survival in patients with endometrioid or serous endometrial cancers (221)

Objectives: We sought to determine the interaction between pathologic and histologic features and impact on overall survival (OS) among patients with endometrial cancer classified by the four molecular subtypes, identified by The Cancer Genome Atlas (TCGA). Methods: Using TCGA’s Pan-Cancer Atlas accessed via the cBioPortal, we identified patients with endometrioid or serous endometrial cancer. Patients with available molecular data were included in our analysis. We recorded available outcomes data, and FIGO stage and pathologic factors were manually extracted from surgical pathology reports. OS was compared among groups using Kaplan-Meier curves. Results: A total of 507 patients with molecularly subtyped endometrioid or serous endometrial cancers were identified. FIGO stage was inferred using surgical pathology reports, and data regarding LVSI and histologic grade were available in 467 patients. Tumors were categorized as POLE hypermutated (43/467; 9.2%), microsatellite instable (MSI) hypermutated (139/467; 29.8%), copy number low (CN-low) (142/467; 30.4%), and CN-high (143/467; 30.6%). While molecular subtype was significantly correlated with OS among the entire study population (p <0.0001), this correlation was only significant among stage III tumors when divided by FIGO stages (n=100, p = 0.012). Increasing histologic grade was associated with worse OS among patients with CN-low tumors (5-year survival: G1 100%, G2 88%, G3 59.4%; p = 0.0051) but not among patients with other TCGA molecular subtypes or low-grade tumors. Of the 73 patients with CN-high tumors with LVSI, 32 (43.8%) were node-positive. Of the 35 patients with CN-low tumors with LVSI, four (11.4%) were node-positive. The presence of LVSI was associated with worse OS than those without LVSI among patients with CN-high (3-year survival rate: 56.9% vs 83.1%, p = 0.0048) and CN-low (3-year survival rate: 88.5% vs 94.4%, p = 0.0024) tumors. Conclusions: In this cohort of patients with endometrioid and serous endometrial cancer from the TCGA, the presence of LVSI was associated with worse OS among patients with CN-low and CN-high tumors. Patients with CN-low tumors with LVSI were less likely to be node positive than patients with CN-high tumors with LVSI. Increasing histologic grade was associated with worse OS only among patients with CN-low tumors. These data support a combined molecular histopathologic classification for prognosis in endometrial cancer. Objectives: We sought to determine the interaction between pathologic and histologic features and impact on overall survival (OS) among patients with endometrial cancer classified by the four molecular subtypes, identified by The Cancer Genome Atlas (TCGA). Methods: Using TCGA’s Pan-Cancer Atlas accessed via the cBioPortal, we identified patients with endometrioid or serous endometrial cancer. Patients with available molecular data were included in our analysis. We recorded available outcomes data, and FIGO stage and pathologic factors were manually extracted from surgical pathology reports. OS was compared among groups using Kaplan-Meier curves. Results: A total of 507 patients with molecularly subtyped endometrioid or serous endometrial cancers were identified. FIGO stage was inferred using surgical pathology reports, and data regarding LVSI and histologic grade were available in 467 patients. Tumors were categorized as POLE hypermutated (43/467; 9.2%), microsatellite instable (MSI) hypermutated (139/467; 29.8%), copy number low (CN-low) (142/467; 30.4%), and CN-high (143/467; 30.6%). While molecular subtype was significantly correlated with OS among the entire study population (p <0.0001), this correlation was only significant among stage III tumors when divided by FIGO stages (n=100, p = 0.012). Increasing histologic grade was associated with worse OS among patients with CN-low tumors (5-year survival: G1 100%, G2 88%, G3 59.4%; p = 0.0051) but not among patients with other TCGA molecular subtypes or low-grade tumors. Of the 73 patients with CN-high tumors with LVSI, 32 (43.8%) were node-positive. Of the 35 patients with CN-low tumors with LVSI, four (11.4%) were node-positive. The presence of LVSI was associated with worse OS than those without LVSI among patients with CN-high (3-year survival rate: 56.9% vs 83.1%, p = 0.0048) and CN-low (3-year survival rate: 88.5% vs 94.4%, p = 0.0024) tumors. Conclusions: In this cohort of patients with endometrioid and serous endometrial cancer from the TCGA, the presence of LVSI was associated with worse OS among patients with CN-low and CN-high tumors. Patients with CN-low tumors with LVSI were less likely to be node positive than patients with CN-high tumors with LVSI. Increasing histologic grade was associated with worse OS only among patients with CN-low tumors. These data support a combined molecular histopathologic classification for prognosis in endometrial cancer.

Machine Learning for Endometrial Cancer Prediction and Prognostication.

Endometrial cancer (EC) is a prevalent uterine cancer that remains a major contributor to cancer-associated morbidity and mortality. EC diagnosed at advanced stages shows a poor therapeutic response. The clinically utilized EC diagnostic approaches are costly, time-consuming, and are not readily available to all patients. The rapid growth in computational biology has enticed substantial research attention from both data scientists and oncologists, leading to the development of rapid and cost-effective computer-aided cancer surveillance systems. Machine learning (ML), a subcategory of artificial intelligence, provides opportunities for drug discovery, early cancer diagnosis, effective treatment, and choice of treatment modalities. The application of ML approaches in EC diagnosis, therapies, and prognosis may be particularly relevant. Considering the significance of customized treatment and the growing trend of using ML approaches in cancer prediction and monitoring, a critical survey of ML utility in EC may provide impetus research in EC and assist oncologists, molecular biologists, biomedical engineers, and bioinformaticians to further collaborative research in EC. In this review, an overview of EC along with risk factors and diagnostic methods is discussed, followed by a comprehensive analysis of the potential ML modalities for prevention, screening, detection, and prognosis of EC patients.

Prognostic values of human epididymis protein 4 expression in patients with endometrial cancer: A systematic review and meta-analysis.

There is no consensus on the correlation between human epididymis protein 4 (HE4) and prognosis of endometrial cancer (EC). Therefore, we performed a meta-analysis to assess the relationship between HE4 and prognosis of EC. In this systematic review and meta-analysis, the databases were searched. Correlation of serum or tissue HE4 with clinicopathological characteristics was determined by odds ratio (OR) or standardized mean difference (SMD) with 95% confidence interval (CI), respectively. The hazard ratio (HR) with 95% CI was calculated to evaluate the correlation between HE4 and survival outcome. A total of 38 published studies were eligible. We found that high levels of serum HE4 were associated with FIGO III-IV stage (SMD=1.58, 95%CI: 1.18-1.98, p < 0.001), grade 3 (SMD=0.66, 95%CI: 0.39-0.93, p=0.001), ≥50% myometrial invasion (SMD=0.78, 95%CI: 0.58-0.99, p < 0.001), lymphovascular space invasion (SMD=0.82, 95%CI: 0.54-1.11, p=0.001), lymph node metastasis (SMD=1.27, 95%CI: 0.84-1.69, p < 0.001), cervical involvement (SMD=0.71, 95%CI: 0.43-0.98, p=0.003), parametrial involvement (SMD=1.03, 95%CI: 0.71-1.35, p < 0.001) and peritoneal cytology (SMD=0.49, 95%CI: 0.22-0.75, p < 0.001). High expression of tissue HE4 was only significantly associated with lymph node metastasis (OR=6.19, 95%CI: 2.07-18.50, p=0.001). High levels of serum HE4 were significantly associated with poor overall survival (univariate: HR=3.77, 95%CI: 1.94-7.32, p < 0.001; multivariate: HR=2.15, 95%CI: 1.65-2.80, p < 0.001) and disease-free survival (univariate: HR=2.89, 95%CI: 2.14-3.88, p < 0.001; multivariate: HR=2.31, 95%CI:1.20-2.67, p < 0.001) in EC. Compared with cancer antigen 125, serum HE4 may be a better prognostic indicator for EC. High HE4 expression is associated with poor prognosis of EC and may be a potential prognostic biomarker for EC.

Construction of a miRNA-Based Nomogram Model to Predict the Prognosis of Endometrial Cancer.

Objective: To investigate the differential expression of microRNA (miRNA) in patients with endometrial cancer and its relationship with prognosis and survival. Method: We used The Cancer Genome Atlas (TCGA) database to analyze differentially expressed miRNAs in endometrial cancer tissues and adjacent normal tissues. In addition, we successfully screened out key microRNAs to build nomogram models for predicting prognosis and we performed survival analysis on the key miRNAs as well. Result: We identified 187 differentially expressed miRNAs, which includes 134 up-regulated miRNAs and 53 down-regulated miRNAs. Further univariate Cox regression analysis screened out 47 significantly differentially expressed miRNAs and selected 12 miRNAs from which the prognostic nomogram model for ECA patients by LASSO analysis was constructed. Survival analysis showed that high expression of hsa-mir-138-2, hsa-mir-548f-1, hsa-mir-934, hsa-mir-940, and hsa-mir-4758 as well as low-expression of hsa-mir-146a, hsa-mir-3170, hsa-mir-3614, hsa-mir-3616, and hsa-mir-4687 are associated with poor prognosis in EC patients. However, significant correlations between the expressions levels of has-mir-876 and hsa-mir-1269a and patients’ prognosis are not found. Conclusion: Our study found that 12 significantly differentially expressed miRNAs might promote the proliferation, invasion, and metastasis of cancer cells by regulating the expression of upstream target genes, thereby affecting the prognosis of patients with endometrial cancer.

The prognosis of endometrial cancers stratified with conventional risk factors and modified molecular classification.

This study aimed to validate the Proactive Molecular Risk Classifier for Endometrial Cancer, a modified version of The Cancer Genome Atlas, using data from 184 patients with endometrial cancer (median age: 57.5 years; median follow‐up period: 109 months) who had undergone radical surgery (including systemic lymphadenectomy) and subsequent adjuvant chemotherapy (patients with intermediate or high recurrence risk) from 2003 to 2015. Tissue microarrays were prepared from surgical specimens and classified using the conventional clinical risk classifier. Immunohistochemistry was used to detect mismatch repair proteins, L1 cell adhesion molecule, and p53. Direct sequencing was used to identify hotspot mutations in the polymerase‐epsilon gene. Forty‐five patients were identified as having high L1 cell adhesion molecule expression, 41 as low risk, 34 as mismatch repair‐deficient, 13 as polymerase‐epsilon gene‐mutated, five as having abnormal p53, and 46 as other. Patients were stratified into significantly different prognostic groups (p < 0.0001): favorable (low risk and polymerase‐epsilon gene‐mutated), intermediate (mismatch repair‐deficient and other), and unfavorable (high L1 cell adhesion molecule expression and abnormal p53) with 5‐year disease‐specific survival rates of 100%, 93.8%, and 75.1%, respectively (Kaplan–Meier method). The combination of conventional recurrent risk classification, sequencing for polymerase‐epsilon gene mutations and immunohistochemistry for L1 cell adhesion molecule, p53, and mismatch repair proteins can be used to determine the prognoses of patients with endometrial cancer.

BHLHE22 Expression Is Associated with a Proinflammatory Immune Microenvironment and Confers a Favorable Prognosis in Endometrial Cancer.

Endometrial cancer (EC) rates are rising annually. Additional prediction markers need to be evaluated because only 10–20% of EC cases show an objective response to immune-checkpoint inhibitors (ICIs). Our previous methylomic study found that BHLHE22 is hypermethylated in EC tissues and can be detected using a Pap-smear sample. BHLHE22, a basic helix loop helix transcription factor family member, is known as a transcriptional repressor and is involved in cell differentiation. However, the role of BHLHE22 in EC remains poorly understood. Herein, we analyzed BHLHE22 expression in 54 paired cancer and normal endometrial tissue samples, and confirmed with databases (TCGA, GTEx, and human protein atlas). We found that BHLHE22 protein expression was significantly downregulated in EC compared with normal endometrium. High BHLHE22 expression was associated with microsatellite-instable subtype, endometrioid type, grade, and age. It showed a significant favorable survival. BHLHE22 overexpression inhibited the proliferation and migration of EC cells. Functional enrichment analysis showed that BHLHE22 was significantly associated with immune-related pathways. Furthermore, BHLHE22 was positively correlated with proinflammatory leukocyte infiltration and expression of chemokine genes in EC. In conclusion, BHLHE22 regulates immune-related pathways and modulates the immune microenvironment of EC.

Association of Tumor Size With Prognosis in Patients With Resectable Endometrial Cancer: A SEER Database Analysis.

This study aimed to explore the relationship between tumor size (Ts) and prognosis in endometrial cancer (EC). A total of 52,208 patients with EC who underwent total hysterectomy were selected from the Surveillance, Epidemiology, and End Results Program database. Overall survival (OS) and endometrial cancer-specific survival (ESS) were chosen as survival outcomes. The Cox proportional hazards model was used to explore the effect of Ts on prognosis. The restricted cubic splines based on the Cox regression model were used to determine the nonlinear relationship between Ts and survival. When Ts was analyzed as a categorical variable, the risk of death increased with Ts, with the highest risk in patients with Ts > 9 cm with regard to all-cause death (ACD) (hazard ratio [HR] 1.317; 95% confidence interval [CI], 1.196-1.450; P < 0.001) and endometrial cancer-specific death (ESD) (HR, 1.378; 95% CI, 1.226-1.549; P < 0.001). As a continuous variable, Ts showed a nonlinear relationship with ACD (HR, 1.061; 95% CI, 1.053-1.069; P < 0.001) and ESD (HR, 1.062; 95% CI, 1.052-1.073; P < 0.001). The risk of mortality increased quickly with Ts when Ts was less than 7.5 cm and then leveled off when Ts was larger than 7.5 cm in all patients. Among patients with lymph node metastasis, the risk of poor prognosis decreased rapidly with Ts when Ts was less than 3.5 cm, and subsequently increased sharply with Ts when Ts ranged from 3.5 cm to 7.5 cm, and then increased slowly when Ts was larger than 7.5 cm (P < 0.001 for nonlinearity). There was a nonlinear relationship between Ts and prognosis in patients with EC. Clinicians should not ignore the impact of small tumors on prognosis in EC patients with lymph node metastasis.

Integrated Bioinformatic Analysis of DNA Methylation and Immune Infiltration in Endometrial Cancer.

Background Endometrial cancer greatly threatens the health of female. Emerging evidences have demonstrated that DNA methylation and immune infiltration are involved in the occurrence and development of endometrial cancer. However, the mechanism and prognostic biomarkers of endometrial cancer are still unclear. In this study, we assess DNA methylation and immune infiltration via bioinformatic analysis. Methods The latest RNA-Seq, DNA methylation data, and clinical data related to endometrial cancer were downloaded from the UCSC Xena dataset. The methylation-driven genes were selected, and then the risk score was obtained using “MethylMix” and “corrplot” R packages. The connection between methylated genes and the expression of screened driven genes were explored using “survminer” and “beeswarm” packages, respectively. Finally, the role of VTCN1in immune infiltration was analyzed using “CIBERSORT” package. Results In this study, 179 upregulated genes, and 311 downregulated genes were identified and found to be related to extracellular matrix organization, cell–cell junctions, and cell adhesion molecular binding. The methylation-driven gene VTCN1 was selected, and patients classified to the hypomethylation and high expression group displayed poor prognosis. The VTCN1 gene exhibited highest correlation coefficient between methylation and expression. More importantly, the hypomethylation of promoter of VTCN1 led to its high expression, thereby induce tumor development by inhibiting CD8+ T cell infiltration. Conclusions Overall, our study was the first to reveal the mechanism of endometrial cancer by assessing DNA methylation and immune infiltration via integrated bioinformatic analysis. In addition, we found a pivotal prognostic biomarker for the disease. Our study provides potential targets for the diagnosis and prognosis of endometrial cancer in the future.