Endometrioid Endometrial Carcinoma Patients Research Articles

Validating the 2023 FIGO staging system: A nomogram for endometrioid endometrial cancer and adenocarcinoma.

To find the factors impacting overall survival (OS) prognosis in patients with endometrioid endometrial carcinoma (EEC) and adenocarcinoma and to establish a nomogram model to validate the 2023 International Federation of Obstetrics and Gynecology (FIGO) staging system for endometrial cancer. Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) training cohort. An independent validation cohort was obtained from the First Affiliated Hospital of Anhui Medical University between 2008 and 2023. Cox regression analysis identified independent prognostic factors for OS in EEC and adenocarcinoma patients. A nomogram predicting OS was developed and validated utilizing the C-index, calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). The relationship between the tumor grade and prognosis of EEC and adenocarcinoma was quantified using net reclassification improvement (NRI), propensity score matching (PSM), and Kaplan-Meier curves. Cox regression analysis identified age, race, marital status, tumor grade, tumor stage, tumor size, and chemotherapy as independent prognostic factors for OS. A nomogram for predicting OS was developed based on these factors. The C-indexes for the OS nomogram was 0.743 and 0.720 for the SEER training set and external validation set, respectively. The area under the ROC (AUC) for the OS nomogram was 0.755, 0.757, and 0.741 for the SEER data subsets and 0.844, 0.719, and 0.743 for the external validation subsets. Calibration plots showed high concordance between the nomogram-predicted and observed OS. DCA also demonstrated the clinical utility of the OS nomogram. NRI, PSM, and survival analyses revealed that tumor grade was the most important histopathological factor for EEC and adenocarcinoma prognosis. Seven independent prognostic variables for the OS of patients with EEC and adenocarcinoma were identified. The established OS nomogram has good predictive ability and clinical utility and validates the 2023 endometrial cancer FIGO staging system.

Endometrioid Endometrial RNA Index Predicts Recurrence in Stage I Patients.

Risk prediction with genomic and transcriptomic data has the potential to improve patient outcomes by enabling clinicians to identify patients requiring adjuvant treatment approaches, while sparing low-risk patients from unnecessary interventions. Endometrioid endometrial carcinoma (EEC) is the most common cancer in women in developed countries, and rates of endometrial cancer are increasing. We collected a 105-patient case-control cohort of stage I EEC comprised of 45 patients who experienced recurrence less than 6 years after excision, and 60 FIGO grade matched controls without recurrence. We first utilized two RNA based, previously validated machine learning approaches, namely EcoTyper and Complexity Index in Sarcoma (CINSARC). We developed Endometrioid Endometrial RNA Index (EERI) which uses RNA expression data from 46 genes to generate a personalized risk score for each patient. EERI was trained on our 105-patient cohort and tested on a publicly available cohort of 263 stage I EEC patients. EERI was able to predict recurrences with 94% accuracy in the training set and 81% accuracy in the test set. In the test set, patients assigned as EERI high-risk were significantly more likely to experience recurrence (30%) than the EERI low-risk group (1%) with a hazard ratio of 9.9 (95% CI 4.1-23.8, P <0.001). Tumors with high-risk genetic features may require additional treatment or closer monitoring and are not readily identified using traditional clinicopathologic and molecular features. EERI performs with high sensitivity and modest specificity, which may benefit from further optimization and validation in larger independent cohorts.

TTN Mutation in Endometrial Endometrioid Carcinoma Is Associated with Poor Clinical Outcomes and High Tumor Mutation Burden

Endometrioid endometrial carcinoma (EEC) stands as a prevalent gynecologic malignancy in developed regions. However, predicting relapse cases remains challenging, necessitating the identification of a novel biomarker for EEC relapse. The assessment of tumor mutational burden (TMB) is pivotal for immunotherapy in EEC patients. However, both whole-exome sequencing (WES) and targeted sequencing encountered application-related difficulties. In light of this, standardized and simplified techniques for TMB measurement are imperative. In this study, we employed WES on 25 EEC patients (12 relapsed cases and 13 non-relapsed cases) who accepted hysterectomy surgery (CHCAMS cohort). We additionally obtained a total of 391 tumor samples with clinicopathological features from TCGA website to broaden the study cohort. In the CHCAMS cohort, the TTN mutant group showed shorter progression-free survival (p < 0.001) and overall survival (p < 0.001) than TTN wild-type group. Additionally, we discovered that the number of TTN mutations per sample was significantly linked with TMB-WES in CHCAMS cohort and TCGA cohort (p < 0.05). And the number of TTN mutations per sample in POLE mutant group was greater than in the POLE wild-type group (p < 0.0001). In conclusion, TTN mutation may serve as a biomarker for EEC prognosis. TTN mutation is also associated with WES-TMB, and could be a simplified TMB measurement technique.

Mechanisms of mutant β-catenin in endometrial cancer progression.

Endometrial carcinoma (EC) is the most diagnosed gynecological malignancy in Western countries. Both incidence and mortality rates of EC have steadily risen in recent years. Despite generally favorable prognoses for patients with the endometrioid type of EC, a subset of patients has been identified with decreased progression-free survival. Patients in this group are distinguished from other endometrioid EC patients by the presence of exon 3 hotspot mutations in CTNNB1, the gene encoding for the β-catenin protein. β-catenin is an evolutionarily conserved protein with critical functions in both adherens junctions and Wnt-signaling. The exact mechanism by which exon 3 CTNNB1 mutations drive EC progression is not well understood. Further, the potential contribution of mutant β-catenin to adherens junctions’ integrity is not known. Additionally, the magnitude of worsened progression-free survival in patients with CTNNB1 mutations is context dependent, and therefore the importance of this subset of patients can be obscured by improper categorization. This review will examine the history and functions of β-catenin, how these functions may change and drive EC progression in CTNNB1 mutant patients, and the importance of this patient group in the broader context of the disease.

Spatial expression of the FGFR2b splice isoform and its prognostic significance in endometrioid endometrial carcinoma.

Endometrial carcinoma (EC) is the most common gynecological malignancy and fibroblast growth factor receptor 2 (FGFR2) is a frequently dysregulated receptor tyrosine kinase. FGFR2b and FGFR2c are the two main splice isoforms of FGFR2 and are normally localized in epithelial and mesenchymal cells, respectively. Previously, we demonstrated that FGFR2c mRNA expression was associated with aggressive tumor characteristics, shorter progression‐free survival (PFS), and disease‐specific survival (DSS) in endometrioid ECs (EECs). The objectives of this study were to investigate the spatial expression of FGFR2b in normal and hyperplasia with and without atypia of human endometrium and to assess the prognostic significance of FGFR2b expression in EC. FGFR2b and FGFR2c mRNA expression was evaluated in normal (proliferative [n = 10], secretory [n = 15], and atrophic [n = 10] endometrium), hyperplasia with and without atypia (n = 19) as well as two patient cohorts of EC samples (discovery [n = 78] and Vancouver [n = 460]) using isoform‐specific BaseScope RNA in situ hybridization assays. Tumors were categorized based on FGFR2 isoform expression (one, both, or neither) and categories were correlated with clinicopathologic markers, molecular subtypes, and clinical outcomes. The FGFR2b splice isoform was exclusively expressed in the epithelial compartment of normal endometrium and hyperplasia without atypia. We observed FGFR2c expression at the basalis layer of glands in 33% (3/9) of hyperplasia with atypia. In patients with EEC, FGFR2b+/FGFR2c− expression was found in 48% of the discovery cohort and 35% of the validation Vancouver cohort. In univariate analyses, tumors with FGFR2b+/FGFR2c− expression had longer PFS (hazard ratio [HR] 0.265; 95% CI 0.145–0.423; log‐rank p < 0.019) and DSS (HR 0.31; 95% CI 0.149–0.622; log‐rank p < 0.001) compared to tumors with FGFR2b−/FGFR2c+ expression in the large EEC Vancouver cohort. In multivariable Cox regression analyses, tumors with FGFR2b+/FGFR2c− expression were significantly associated with longer DSS (HR 0.37; 95% CI 0.153–0.872; log‐rank p < 0.023) compared to FGFR2b−/FGFR2c+ tumors. In conclusion, FGFR2b+/FGFR2c− expression is associated with favorable clinicopathologic markers and clinical outcomes suggesting that FGFR2b could play a role in tailoring the management of EEC patients in the clinic if these findings are confirmed in an independent cohort.

Clinical implications of morular metaplasia in fertility-preserving treatment for atypical endometrial hyperplasia and early endometrial carcinoma patients

ObjectiveMorular metaplasia (MM) is a benign epithelial metaplasia that sometimes appears in atypical endometrial hyperplasia (AEH) and endometrioid endometrial carcinoma (EEC). However, the clinical implications of MM for fertility-preserving treatment in AEH and EEC patients are unclear. This study investigated the clinical features and impact of MM on the efficacy of fertility-preserving treatment.MethodsWe retrospectively studied 427 AEH and EEC patients who received fertility-preserving treatment. Clinical features, treatment efficacy, and onco-fertility results were compared between patients with and without MM.ResultsMM appeared in 147 of 427 (34.4%) patients. Among them, 49 (33.3%) had MM only before treatment (BEF group), 32 (21.8%) had sustained MM before and during treatment (SUS group), and 66 (44.9%) had MM only during treatment (DUR group). The BEF group had a higher 12-month CR rate (98.0% vs 85.7%, p = 0.017) and shorter therapeutic duration to achieve CR (4.0 vs 5.7 months, p = 0.013) than the non-MM group had. In comparison with the non-MM group, the SUS and DUR groups had a lower CR rate after 7 months of treatment (SUS vs non-MM, 37.5% vs 61.1%, p = 0.010; DUR vs non-MM 33.3% vs. 61.1%, p < 0.001), and a longer median therapeutic duration to achieve CR (SUS vs non-MM, 7.6 vs. 4.0 months, p = 0.037; DUR vs non-MM, 7.9 vs. 4.0 months, p < 0.001).ConclusionAppearance of MM only before treatment was positively correlated with outcome of fertility-preserving treatment, while sustained MM or appearance of MM only during treatment implied poorer outcome of fertility-preserving treatment in AEH and EEC patients.

Hysteroscopic Curettage Followed by Megestrol Acetate Plus Metformin as a Fertility-Sparing Treatment for Women with Atypical Endometrial Hyperplasia or Well-Differentiated Endometrioid Endometrial Carcinoma.

Background:In reproductive-aged women, the incidence of atypical endometrial hyperplasia (AEH) or endometrioid endometrial carcinoma (EEC) is rising globally. The study aimed to investigate the effectiveness of hysteroscopic curettage followed by megestrol acetate (MA) plus metformin as conservative treatment in AEH and early EEC.Methods:We retrospectively studied AEH and stage IA, grade 1 EEC patients treated with hysteroscopic curettage followed by MA (160 mg/d) plus metformin (1500 mg/d) from January 2010 to December 2020 at Fudan University Shanghai Cancer Center. Treatment outcomes were assessed by complete response (CR) rate, recurrence rate, and pregnancy outcomes. Univariate and multivariate analyses were performed via the logistic regression model.Results:The study included 79 patients, 31 (39.2%) with AEH and 48 (60.8%) with EEC. The medians of age (years) and follow-up time (months) were 30 and 39.5, respectively. Seventy-six patients (96.2%) finally achieved CR. The median time to CR was 3.6 (3.0-20.6) months. The CR rate after 3 months, 6 months, and 1 year was 55 (69.6%), 67 (84.8%), and 72 (91.1%), respectively. Recurrence occurred in 26 (34.2%) patients. Treatment duration ⩾9 months was associated with a lower recurrence rate after CR (P = .012). Fourteen (93.3%) of the 15 recurrent patients who received progestin re-treatment achieved CR again. Finally, 29 patients delivered live births.Conclusions:Hysteroscopy followed by MA plus metformin can achieve CR in short time and is overall safe. Consolidation treatment should be prolonged to decrease the recurrence rate, despite a shorter time to CR.

N-methyladenosine reader YTHDF2-mediated long noncoding RNA FENDRR degradation promotes cell proliferation in endometrioid endometrial carcinoma

Dysregulation of long noncoding RNA (LncRNA) FENDDR has been shown to be closely related to the progression of several cancers. However, its role and upstream regulatory mechanism in endometrioid endometrial carcinoma (EEC) remains unclear. This study was conducted using the cancerous tissues of EEC patients (n = 60), EEC cell lines, and a xenograft mouse model. The expression level of LncRNA FENDRR was decreased and the N-methyladenosine (m6A) methylation levels of LncRNA FENDRR was elevated in cancerous tissues of EEC patients. In vitro experiments demonstrated that YTH domain-containing 2 (YTHDF2), an m6A reader, recognized the abundance of m6A-modified LncRNA FENDRR in EEC cells and promoted its degradation. LncRNA FENDRR overexpression suppressed cell proliferation and facilitated cell apoptosis in the EEC cell line HEC-1B by reducing the protein level of SRY-related HMG box transcription factor 4 (SOX4). Interference of LncRNA FENDRR reversed the inhibitory effect of sh-YTHDF2 on cell proliferation and the promoting effect of sh-YTHDF2 on cell apoptosis in HEC-1B cells by silencing FENDRR. Finally, in vivo experiments confirmed that overexpression of LncRNA FENDRR retarded the growth of EEC cells. In conclusion, YTHDF2-mediated LncRNA FENDRR degradation promotes cell proliferation by elevating SOX4 expression in EEC.

Loss of ARID1A Expression as a Favorable Prognostic Factor in Early-Stage Grade 3 Endometrioid Endometrial Carcinoma Patients.

Introduction: High-risk patients with grade 3 endometrioid endometrial carcinoma (G3EEC) who require adjuvant therapy have not been clearly identified. Therefore, the current study aimed to investigate the prognostic impact of ARID1A, p53, and mismatch repair (MMR) protein expressions, previously reported as prognosticators in some gynecological cancers, in patients with early-stage G3EEC. Methods: A total of 67 patients with pathologically confirmed early-stage G3EEC diagnosed between 1997 and 2020 were identified; none received adjuvant chemotherapy. The recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared with a log-rank test. The protein expressions of ARID1A, p53, and MMR were examined via immunohistochemistry, and the associations between these biomarkers and clinical outcomes were evaluated. Results: Recurrence was observed in 9 (13%) of the 67 patients with early stage G3EEC. The respective 5-years RFS and OS rates were 87.7% and 93.7%, and 68.6% and 85.7%, respectively for stages I and II. Multivariate analysis showed significantly longer RFS among patients with ARID1A loss (hazard ratio = 8.7; 95% CI, 1.09–69.6, p = 0.04). No significant differences were observed in RFS and OS of patients according to p53 and MMR expression status. Conclusion: ARID1A expression status was a prognosticator for patients with early stage G3EEC without adjuvant therapy, whereas p53 and MMR expression status showed no impact on survival outcomes. ARID1A may become a useful biomarker for stratification of adjuvant treatment for early stage G3EEC patients.

Preoperative predictive factor analysis of ovarian malignant involvement in premenopausal patients with clinical stage I endometrioid endometrial carcinoma

Earlier literature suggests that ovarian preservation in young premenopausal clinical stage I endometrioid endometrial carcinoma patients does not negatively impact prognosis. The main purpose of this study was to clarify the incidence of ovarian malignant involvement in this group and further identify potential preoperative predictive factors of ovarian malignant involvement. A total of 511 premenopausal (age ≤ 50 years) patients were enrolled for the study at Women’s Hospital, Zhejiang University School of Medicine, between January 2002 and December 2016. Ovarian malignant involvements were detected in 23 of the patients (4.5%). Univariate and multivariate logistic analysis validated preoperative imaging of myometrial invasion depth and preoperative serum carbohydrate antigen 125 (CA125) level as independent risk predictors of postoperative ovarian malignant involvement. Receiver operating characteristic (ROC) curves was generated for a combination of the two factors. The area under curve (AUC) was 0.772 (95% confidence interval [CI] 0.661–0.884) for the combined two factors. The incidence of postoperative ovarian malignant involvement was relatively minimal. Preoperative imaging of myometrial invasion depth and serum CA125 level were independent risk predictors of ovarian malignant involvement. These findings may facilitate preoperative counseling of patients and informed clinical decision-making on ovarian preservation in these patients.

Low Red Blood Cell Count as an Early Indicator for Myometrial Invasion in Women with Endometrioid Endometrial Carcinoma with Metabolic Syndrome.

PurposeWe investigated the relationship between metabolic syndrome (MetS) and its components and erythrocyte parameters such as red blood cell count (RBC) and hemoglobin (Hb) levels, and their association with the risk of deep myometrial invasion in endometrioid endometrial carcinoma (EEC).Patients and MethodsA total of 473 women diagnosed with EEC between January 2012 and December 2018 were included in the study. MetS was diagnosed using a modified version of the Chinese Diabetes Society 2004 criteria. Demographic and clinical characteristics were stratified by MetS and compared. Logistic regression analyses were performed to calculate the odds ratios (ORs) of myometrial invasion.ResultsThe prevalence of MetS was 18.8% (89/473). RBC and Hb levels were significantly higher in EEC patients with MetS. RBC and Hb values increased linearly with the number of MetS components. The OR of the MetS risk increased across the RBC quartiles (OR=2.212, 95% confidence interval [Cl]=1.125-4.350, P˂0.05). Among EEC patients with MetS, the OR of deep myometrial invasion increased with the decrease of the RBC quartiles (P=0.037). Similarly, in EEC patients with obesity and hyperglycemia or with ≥2 MetS criteria, the lowest RBC level (Q1) was a risk factor for deep myometrial invasion compared with the reference RBC group (Q4, P˂0.05). However, this trend was not evident in EEC patients without MetS and its components.ConclusionEEC with MetS and its components had higher RBC and Hb levels. The association between the erythrocyte parameters and myometrial invasion differed with MetS. RBC was identified as a risk factor of myometrial invasion in EEC patients with MetS and its components.

A prospective multicenter international single-arm observational study on the oncological safety of the sentinel lymph node algorithm in stage I intermediate-risk endometrial cancer (SELECT, SEntinel Lymph node Endometrial Cancer Trial)

BackgroundIn the primary treatment of apparent uterine-confined endometrial carcinoma, pelvic ± para-aortic lymphadenectomy has been considered the standard of care. Although some retrospective data suggest that the sentinel lymph node...

Overexpression of HMGA1 Figures as a Potential Prognostic Factor in Endometrioid Endometrial Carcinoma (EEC).

Endometrioid endometrial carcinomas (EEC) are the most common malignant gynecologic tumors. Despite the increase in EEC molecular knowledge, the identification of new biomarkers involved in disease’s development and/or progression would represent an improvement in its course. High-mobility group A protein (HMGA) family members are frequently overexpressed in a wide range of malignancies, correlating with a poor prognosis. Thus, the aim of this study was to analyze HMGA1 and HMGA2 expression pattern and their potential role as EEC biomarkers. HMGA1 and HMGA2 expression was initially evaluated in a series of 46 EEC tumors (stages IA to IV), and the findings were then validated in The Cancer Genome Atlas (TCGA) EEC cohort, comprising 381 EEC tumors (stages IA to IV). Our results reveal that HMGA1 and HMGA2 mRNA and protein are overexpressed in ECC, but only HMGA1 expression is associated with increased histological grade and tumor size. Moreover, HMGA1 but not HMGA2 overexpression was identified as a negative prognostic factor to EEC patients. Finally, a positive correlation between expression of HMGA1 pseudogenes—HMGA1-P6 and HMGA1-P7—and HMGA1 itself was detected, suggesting HMGA1 pseudogenes may play a role in HMGA1 expression regulation in EEC. Thus, these results indicate that HMGA1 overexpression possesses a potential role as a prognostic biomarker for EEC.

Can morphometric analysis of the fallopian tube fimbria predict the presence of uterine papillary serous carcinoma (UPSC)?

Uterine serous papillary carcinoma (UPSC) is an aggressive tumor, often diagnosed as a metastatic disease and characterized by a high recurrence rate and poor prognosis. UPSC represents a distinct subtype of endometrial cancer which is different in clinical and pathological behaviors from endometrioid endometrial carcinoma (EEC) and resembles more to serous ovarian carcinoma. Since tumors of serous papillary of the ovary are hypothesized to stem from cells of the fallopian tube's fimbria, we hypothesized that UPSC may also origin in the fallopian tubes. In our previous study, using a novel method of computerized morphometry of the fimbrial epithelium we have found significant differences between fimbriae of healthy women and serous ovarian cancer patients. In this study we showed the presence of morphologic differences between twenty-four fimbriae from healthy women, and twenty six fimbriae from uterus cancer (13 from UPSC patients and 13 from EEC patients). All fimbriae reported by the pathologist as "normal" were subjected to a computerized histomorphometric analysis. Two-step method of computerized histomorphometry, i.e. Fast Fourier transformation (FFT) followed by a co-occurrence matrix analysis and an additional analysis of the nuclear symmetry of the tubal fimbrial epithelium were applied. Using these novel methods, we were able to show differences in the morphometric characteristics of the fimbriae in UPSC patients compared to EEC and healthy patients. It is yet to be determined the clinical significance of this observation.

MELF Pattern for Predicting Lymph Node Involvement and Survival in Grade I-II Endometrioid-type Endometrial Cancer.

The aim of this study was to examine the associations between microcystic, elongated, and fragmented (MELF) pattern and other prognostic factors and lymph node involvement, disease-free survival, and overall survival (OS) using a case-control group consisting of grade I-II endometrioid endometrial carcinoma (EEC) patients with/without lymph node involvement. The files of the patients were searched electronically for all hysterectomy specimens with a diagnosis of grade I-II EEC of the uterine body from January 1, 2008 to July 31, 2014. Lymph node involvement was detected in 27 patients who were histologically diagnosed with grade I-II EEC, and these patients made up the case group. Using a dependent random sampling method, 28 grade I-II EEC patients without lymph node involvement were selected. According to multivariate regression analysis, lymphovascular space invasion [odds ratio, 23.5; 95% confidence interval (CI), 2.4-223.5] and MELF pattern (odds ratio, 13.3; 95% CI, 1.4-121.8) were significant predictors of lymph node involvement. There was recurrence in 15.8% of cases that showed a MELF pattern and in 19.4% of those that did not (P=0.738). According to Kaplan-Meier analysis, the MELF pattern revealed no significant differences in disease-free survival (hazard ratio, 1.0; 95% CI, 0.1-36.5), whereas the effect on OS was significant (hazard ratio, 2.2; 95% CI, 1.3-4.2). The presence of MELF pattern was a substantial risk factor for detecting lymph node involvement in patients with grade I-II EEC. The MELF pattern may be important for identifying which patients need staging surgery, in addition to its effect on the OS.

Adjuvant Therapy Use and Survival in Stage II Endometrial Cancer.

Radiotherapy (RT) is an established adjuvant treatment for stage II endometrioid endometrial carcinoma (EEC). The role of chemotherapy (CT) in stage II EEC is less proven. We used the National Cancer Data Base to identify factors associated with adjuvant CT in stage II EEC and to explore whether receipt of CT was associated with improved overall survival (OS). Women diagnosed in 2010 to 2013 with International Federation of Obstetrics and Gynecology stage II EEC (grades 1-3) after hysterectomy and bilateral salpingo-oophorectomy were identified in the National Cancer Data Base. Multivariable logistic regression was used to identify covariates associated with receipt of CT. Overall survival among patients receiving RT, CT, or chemoradiotherapy (CRT) after surgery was compared using Kaplan-Meier estimates, the log-rank test, Cox proportional hazards regression, and propensity score matching. We identified 6102 stage II EEC patients. There were 358 patients (6%) who received adjuvant CT alone and 525 (9%) who received CRT; the remainder received RT alone (n = 1906; 31%) or no adjuvant treatment (n = 3313; 54%). The presence of lymphovascular invasion (odds ratio, 3.58; P < 0.001) and grade 3 disease (odds ratio, 3.40; P < 0.001) was strongly associated with receipt of CT or CRT. The OS at 3 years for the entire cohort was 89%. On multivariable analysis, CT versus RT was associated with worse OS (hazard ratio [HR], 2.12 [95% confidence interval, 1.46-3.06]; P < 0.001), whereas CRT versus RT was not associated with improved OS (HR, 1.07 [95% confidence interval, 0.71-1.62]; P = 0.781). After propensity score matching, there remained no difference in OS between RT and CRT (HR, 1.14; P = 0.614). Patients with stage II EEC have an excellent prognosis, and most undergo observation or receive adjuvant RT in the United States. Receipt of CT (alone or with RT) was not associated with an OS advantage compared with RT alone in this observational cohort. Randomized trials will help clarify the role of CT in stage II patients.

Long non-coding RNA HAND2-AS1 inhibits invasion and metastasis in endometrioid endometrial carcinoma through inactivating neuromedin U

Endometrioid endometrial carcinoma (EEC) is one of the common causes of cancer-related mortality in women. Mounting evidences suggest that long noncoding RNAs (lncRNAs) function in multiple cancers. In this study, we discovered that HAND2-AS1, a lncRNA transcribed antisense adjacent to Heart and Neural Crest Derivatives Expressed 2 (HAND2) in chromosome 4q33-34, is significantly down-regulated in EEC. HAND2-AS1 and HAND2 were frequently down-regulated in EEC tissues, especially in poor differentiated tumor tissues. Down-regulation of HAND2-AS1 and HAND2 was correlated with tumor grade, lymph node metastasis and recurrence of EEC patients. HAND2-AS1 and HAND2 were co-downregulated by promoter DNA hypermethylation in EEC. Overexpression of HAND2-AS1 in EEC cells demonstrated that HAND2-AS1 suppressed migration and invasion of EEC cells. Similarly, overexpression of HAND2 also inhibited migration and invasion EEC cells indicating that HAND2-AS1 and HAND2 had a concordant role in the progression of EEC. However, HAND2 was not regulated by HAND2-AS1 in EEC. Furthermore, the anti-tumorigenic effect of HAND2-AS1 was mediated by down-regulating NMU, which has an oncogenic role in EEC. Our findings therefore provide the first evidence that HAND2-AS1 is a critical tumor suppressor in EEC.

Prognostic impact of CD133 expression in Endometrial Cancer Patients

To assess the impact of CD133 expression on the prognosis of endometrioid endometrial carcinoma (EEC). We retrospectively assessed CD133 expression in tissue microarray of 116 surgically treated FIGO I-III EEC. Tumors with ≥10% of CD133-expressing cells were considered CD133-positive (CD133+). On the basis of CD133 expression, clinical and pathological parameters, progression-free survival (PFS) and overall survival (OS) were evaluated. Of the EEC studied 85.2% showed CD133-expressing cells. Only 61% (n = 66) of EEC presented ≥10% of CD133 expressing cells and were considered CD133+. The mean OS for CD133+ tumour patients was 161 months (95% CI, 154–168) as compared with 146 months (95% CI, 123–160) for those with CD133- tumors (p = 0.012). The mean PFS for CD133+ tumour was 159 months (95% CI, 149–168) as compared with 147 months (95% CI, 132-161) in those with a CD133-tumour (p = 0.014). CD133+ tumours were less likely to have vascular invasion (p = 0.010) and more likely to be well differentiated (p = 0.034). C133+ tumours predicted favorable OS and PFS of EEC patients, with a Hazard Ratio 4.731 (95% CI, 1.251–17.89; p = 0.022). CD133+ tumor status correlates with favorable prognosis of EEC. Our findings are in agreement with studies addressing brain and colorectal tumours.

Abstract 1793: POLE gene mutations confer good progression free survival in Asian women with FIGO grade 3 endometrioid endometrial carcinoma

Abstract Introduction: Endometrial carcinoma (EC) is the most common gynaecological cancer in developed countries. Mortality rates of patients with FIGO grade 3 endometrioid ECs are almost similar to that of uterine serous carcinoma and clear cell carcinoma. In 2013, the Cancer Tumour Genome Atlast (TGCA) identified POLE gene mutations in a subset of ECs, predominantly in the endometrioid subtype with high FIGO grade. While it has been suggested that POLE mutation confers good prognosis, the data remains conflicting. Our study aims to evaluate the association between the POLE gene mutations and progression free survival in Asian women with FIGO grade 3 endometrioid EC. Methods: Forty-five Asian patients diagnosed with FIGO Grade 3 endometrioid EC between 2009 and 2013 were included. Next generation sequencing (NGS) performed utilizing the Ion Torrent Personal Genome Machine (PGM) and custom designed AmpliSeq panel for formalin fixed embedded (FFPE) tissue was performed. Using the Ion Reporter, mutations with at least 10% allele frequency and present in the COSMIC database were deemed to be pathogenic. All other mutations, excluding silent mutations, were considered as variants of unknown significance (VUS). Survival curves for pathogenic somatic POLE mutated and wild-type tumors were estimated by Kaplan-Meier method and compared using logrank test. Results: All detected pathogenic and VUS POLE gene mutations were missense mutations. Our results provide further evidence to corroborate the mutation effect of POLE gene with 100% recurrence free survival in FIGO Grade 3 endometrioid EC patients with pathogenic POLE gene mutations, extends to South East Asian women as well (median follow-up POLE vs wild type; 52.5 vs 45; p = 0.2). Pathogenic somatic POLE gene mutations were present in 25.5% (12/45) patients with Grade 3 endometrioid EC. All were still alive at the time of censure with no reports of relapse following initial treatment. Three of these women harbored mutations outside exons 9 to 14 with one mutation listed as pathogenic in colorectal carcinomas. Among women without the pathogenic somatic POLE mutation, recurrence was seen in 24.2% (8/33) with 15.1% (5/33) subsequently dying of the disease. Conclusion: POLE gene mutations confer a good prognosis for FIGO grade 3 endometrioid EC and will be important in clinical decision making. POLE wild-type patients potentially show have closer follow-up and should be considered for newer targeted chemotherapeutic agents. Citation Format: Adele Wong, Chik Hong Kuick, Wai Loong Wong, Jill M. Tham, Sorsiah Mansor, Loh Eva, Sudhanshi Jain, Sock Hoai Chan, Sze Huey Tan, Shao Tzu Li, Nadkarni N. Vikas, Sung Hock Chew, Joanne Ngeow, Wanjin Hong. POLE gene mutations confer good progression free survival in Asian women with FIGO grade 3 endometrioid endometrial carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1793.

Tumor progression, metastasis, and modulators of epithelial-mesenchymal transition in endometrioid endometrial carcinoma: an update.

Endometrioid endometrial carcinoma (EEC), also known as type 1 endometrial cancer (EC), accounts for over 70-80% of all cases that are usually associated with estrogen stimulation and often develops in a background of atypical endometrial hyperplasia. The increased incidence of EC is mainly confined to this type of cancer. Most EEC patients present at an early stage and generally have a favorable prognosis; however, up to 30% of EEC present as high risk tumors, which have invaded deep into the myometrium at diagnosis and progressively lead to local or extra pelvic metastasis. The poor survival of advanced EC is related to the lack of effective therapies, which can be attributed to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis. Multiple lines of evidence illustrate that epithelial-mesenchymal transition (EMT)-like events are central to tumor progression and malignant transformation, endowing the incipient cancer cell with invasive and metastatic properties. The aim of this review is to summarize the current knowledge on molecular events associated with EMT in progression, invasion, and metastasis of EEC. Further, the role of epigenetic modifications and microRNA regulation, tumor microenvironment, and microcystic elongated and fragmented glands like invasion pattern have been discussed. We believe this article may perhaps stimulate further research in this field that may aid in identifying high risk patients within this clinically challenging patient group and also lead to the recognition of novel targets for the prevention of metastasis - the most fatal consequence of endometrial carcinogenesis.