p53 Immunohistochemistry staining patterns and prognosis significance in 212 cases of non-endometrioid endometrial cancer.

OBJECTIVE: To investigate the immunohistochemistry (IHC) staining pattern and prognostic significance of p53 in non-endometrioid endometrial cancer (non-EEC). METHODS: This study retrospectively included 212 non-EEC patients, with histological types including serous carcinoma (SC), clear cell carcinoma (CCC), mixed carcinoma (MC), undifferentiated carcinoma (UC), and carcinosarcoma (CS). p53 IHC was interpreted as normal/wild-type and abnormal/mutant-type, the latter including overexpression, complete absence, and cytoplasmic staining patterns. Moreover, uncommon p53 subclonal/heterogeneous staining patterns were described. Disease-free survival (DFS) and overall survival (OS) were employed as endpoints to evaluate the prognostic significance of p53. RESULTS: In 212 non-EEC cases, 50 (23.6 %) were p53 wild-type, while 162 (76.4 %) displayed abnormal p53 staining. Overexpression was the predominant abnormal p53 staining pattern (122/162), complete absence followed (33/162). All SCs exhibited the mutant p53 staining pattern. The p53 abnormal expression rates in CCC, MC, UC, and CS were 37.5 %, 78.9 %, 35.7 %, and 75.7 %, respectively. Interestingly, of the 12 MC cases with SC components, barring one with p53 subclonal staining, all showed the mutant-type staining. The concordance rate for p53 expression between epithelial and mesenchymal components of CS was 94.3 % (66/70). Kaplan-Meier curves indicated patients with p53 abnormalities had worse DFS compared to those with wild-type p53 (P=0.025). Multivariate Cox regression confirmed that p53 (HR: 2.270, 95 % CI: 1.124-4.586, P=0.022) independently predicted DFS in non-EEC patients, though not for OS. CONCLUSIONS: Non-EEC patients with various histological types exhibit different p53 staining patterns. However, abnormal p53 expression, regardless of histological type, implies a poor DFS in non-EEC patients.

Comparison of survival and complications between minimally invasive and open staging surgeries in non-endometrioid endometrial cancer.

OBJECTIVE: This study aimed to compare survival and complications between minimally invasive surgery and open surgery and evaluate related risk factors in patients with non-endometrioid endometrial cancer. METHODS: Clinicopathologic characteristics; survival outcomes; complications; and prognostic factors associated with progression-free survival and overall survival were compared among patients with non-endometrioid endometrial cancer who underwent primary staging surgery using laparoscopic, robotic, or open abdominal surgery (2004-2017). RESULTS: In total, 91 patients were included: 41 and 50 underwent minimally invasive surgery and open surgery, respectively. The minimally invasive surgery and open surgery groups showed similar progression-free survival (5-year progression-free survival rate, 58.7 % vs. 58.5 %; P = .925) and overall survival (5-year overall survival rate, 73.6 % vs. 80.3 %; P = .834). Intraoperative (7.2 % vs. 6.0 %; P = .111) and postoperative surgical complications (14.6 % vs. 26.0 %; P = .165) were similar between the groups. However, blood loss was lower (mean, 305.1 vs. 561.2 ml, P < .001) and hospital stay was shorter (mean, 8.2 vs. 15.4 days, P < .001) in the minimally invasive surgery group. Using multivariate analysis, lymphovascular space invasion was identified as poor prognostic factor for progression-free survival (adjusted hazard ratio [HR], 3.054; 95 % confidence interval [CI], 1.521-6.132; P = .002) and overall survival (adjusted HR, 3.918; 95 % CI, 1.455-10.551; P = .007), whereas age ≥ 60 years was poor prognostic factor for only overall survival (adjusted HR, 5.0953; 95 % CI, 1.660-15.378; P = .004). CONCLUSIONS: Surgical outcomes did not differ between the minimally invasive and open surgery group in patients with non-endometrioid endometrial cancer. Lymphovascular space invasion was a significant survival factor in this context.

Basket study of oral progesterone antagonist onapristone extended release in progesterone receptor-positive recurrent granulosa cell, low-grade serous ovarian cancer, or endometrioid endometrial cancer.

OBJECTIVE: To determine the safety and efficacy of the oral progesterone antagonist onapristone extended release (onapristone-XR) in patients with recurrent progesterone receptor (PR)-positive adult-type granulosa cell tumor (aGCT), low-grade serous ovarian cancer (LGSOC), or endometrioid endometrial cancer (EEC). METHODS: This single-institution phase II study included patients with PR-positive aGCT, LGSOC, or EEC who received ≥1 prior line of chemotherapy. Patients were enrolled from 5/2019-5/2020. PR status was evaluated via immunohistochemistry. Eligible patients had PR expression ≥1% on tissue collected within 3 years of enrollment. Patients received 50 mg of onapristone-XR twice daily until disease progression or treatment discontinuation. Adverse events were graded by Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints were response duration, clinical benefit rate (CBR), and safety. RESULTS: Five patients with LGSOC and 1 with EEC enrolled, but both cohorts closed early due to slow accrual. Fourteen patients with aGCT enrolled and completed stage 1 accrual. No responses were observed. Four patients with LGSOC were evaluable, with median PFS of 4.4 months (range, 1.8-NE) and CBR of 50% (range, 6.8%-93.2%). All 14 patients with aGCT were evaluable, with median PFS of 2.8 months (range, 1.6-4.9), 6-month PFS rate of 21.4% (range, 5.2%-44.8%), 12-month PFS rate of 14.3% (range, 2.3%-36.6%), and a CBR of 35.7% (range, 12.8%-64.9%). CONCLUSIONS: The study did not meet its primary endpoint. While onapristone-XR was well tolerated in all 3 arms, no objective responses were observed.

The roles of tight junction protein cingulin in human endometrioid endometrial cancer.

The bicellular tight junction molecule cingulin (CGN) binds to microtubules in centrosomes. Furthermore, CGN contributes to the tricellular tight junction (tTJ) proteins lipolysis-stimulated lipoprotein receptor (LSR) and tricellulin (TRIC). CGN as well as LSR decreased during the malignancy of endometrioid endometrial cancer (EEC). Although tTJ protein LSR is involved in the malignancy of some cancers, including EEC, the role of CGN is unknown. In this study, we investigated the roles of CGN with tTJ proteins in human EEC cells by using the CGN-overexpressing EEC cell line Sawano. In 2D cultures, CGN was colocalized with LSR and TRIC at tTJ or at γ-tubulin-positive centrosomes. In immunoprecipitation with CGN antibodies, CGN directly bound to LSR, TRIC, and ß-tubulin. Knockdown of CGN by the siRNA decreased the epithelial barrier and enhanced cell proliferation, migration and invasion, as well as knockdown of LSR. In the Sawano cells cocultured with normal human endometrial stromal cells, knockdown of CGN decreased expression of LSR and TRIC via MAPK and AMPK pathways. In 2.5D cultures, knockdown of CGN induced the formation of abnormal cysts and increased the permeability of FD-4 to the lumen. In 2D and 2.5D cultures, treatment with ß-estradiol with or without EGF or TGF-ß decreased CGN expression and the epithelial permeability barrier and enhanced cell migration, and pretreatment with EW7197+AG1478, U0126 or an anti-IL-6 antibody prevented this. In conclusion, CGN, with tTJ proteins might suppress the malignancy of human EEC and its complex proteins are sensitive to estrogen and growth factors derived from stromal cells.

Disease progression, survival, and molecular disparities in Black and White patients with endometrioid endometrial carcinoma in real-world registries and GOG/NRG oncology randomized phase III clinical trials.

OBJECTIVE: Investigate racial disparities in outcomes and molecular features in Black and White patients with endometrioid endometrial carcinoma (EEC). METHODS: Black and White patients diagnosed with EEC who underwent hysterectomy ± adjuvant treatment in SEER, National Cancer Database (NCDB), the Genomics Evidence Neoplasia Information Exchange (GENIE) project (v.13.0), and eight NCI-sponsored randomized phase III clinical trials (RCTs) were studied. Hazard ratio (HR) and 95% confidence interval (CI) were estimated for cancer-related death (CRD), non-cancer death (NCD), and all-cause death. RESULTS: Black (n = 4397) vs. White (n = 47,959) patients in SEER had a HR (95% CI) of 2.04 (1.87-2.23) for CRD and 1.22 (1.09-1.36) for NCD. In NCDB, the HR (95% CI) for death in Black (n = 13,468) vs. White (n = 155,706) patients was 1.52 (1.46-1.58) dropping to 1.29 (1.23-1.36) after propensity-score matching for age, comorbidity, income, insurance, grade, stage, LVSI, and treatment. In GENIE, Black (n = 109) vs. White (n = 1780) patients had fewer PTEN, PIK3R1, FBXW7, NF1, mTOR, CCND1, and PI3K-pathway-related gene mutations. In contrast, TP53 and DNA-repair-related gene mutation frequency as well as tumor mutational burden-high status were similar in Black and White patients. In RCTs, Black (n = 187) vs. White (n = 2877) patients were more likely to have advanced or recurrent disease, higher grade, worse performance status and progressive disease. Risk of death in Black vs. White patients in RCTs was 2.19 (1.77-2.71) persisting to 1.32 (1.09-1.61) after matching for grade, stage, and treatment arm while balancing age and performance status. CONCLUSIONS: Differences exist in clinical presentation, outcomes, and molecular features in Black vs. White patients with EEC in real-world registries and RCTs. Targeted-drug development, strategies to modify social determinants, and diverse inclusion in RCTs are approaches to reduce disparities.

Risk factors for pelvic and para-aortic lymph node metastasis in non-endometrioid endometrial cancer.

PURPOSE: The aim of this study was to evaluate the risk factors for pelvic lymph node metastasis (LNM) and para-aortic LNM in non-endometrioid endometrial cancer (non-EEC). METHODS: A total of 283 patients with non-EEC hospitalized in the First Affiliated Hospital of Zhengzhou University from January 2012 to December 2020 were included. Various characteristics were retrospectively analyzed in relation to LNM. RESULTS: Univariable and multivariable logistic regression analysis revealed cervical stromal invasion (OR = 3.441, 95% CI = 1.558-7.6, p = 0.002), myometrial invasion ≥1/2 (OR = 2.661, 95% CI = 1.327-5.337, p < 0.006), lymphovascular space involvement (LVSI) (OR = 4.118, 95% CI = 1.919-8.837, p < 0.001), positive peritoneal cytology (OR = 2.962, 95% CI = 1.344-6.530, p = 0.007), CA125 (OR = 1.002, 95% CI = 1-1.004, p = 0.026) were the independent risk factors for pelvic LNM. And myometrial invasion ≥1/2 (OR = 5.881, 95% CI = 2.056-16.427, p = 0.001), LVSI (OR = 4.962, 95% CI = 1.933-12.740, p = 0.001), adnexal (OR = 5.921, 95% CI = 2.003-17.502, p = 0.001) were the independent risk factors for para-aortic LNM. With the increase of independent risk factors, the rates of LNM were increased significantly. CONCLUSIONS: Cervical stromal invasion, myometrial invasion ≥1/2, LVSI, positive peritoneal cytology, and CA125 were risk factors for pelvic LNM. Myometrial invasion ≥1/2, LVSI and involvement of the adnexa were risk factors for para-aortic LNM which could provide a good basis to help predict which non-EEC patients are at higher risk for LNM.

Prognostic evaluation of lymph-vascular space invasion in patients with endometrioid and non-endometrioid endometrial cancer: A multicenter study.

INTRODUCTION: The prognostic value of lymph-vascular space invasion (LVSI) on endometrial cancer (EC) remains controversial. This study aimed to explore the impact of LVSI on patients with endometrioid and non-endometrioid EC in China. MATERIALS AND METHODS: We analyzed EC patients who underwent surgery from 2010 to 2019 in seven Chinese hospitals retrospectively and stratified patients based on histopathologic types and LVSI status. Endpoints were disease-free survival (DFS) and overall survival (OS). Propensity score matching (PSM) algorithm was used to balance the confounding factors. The survival was examined using Kaplan-Meier analysis. Cox proportional hazards regression analyses were used to find prognostic independent risk factors. RESULTS: Among 3715 EC patients, LVSI positive rate was 9.31% (346/3715). After matching, LVSI present group had shorter DFS (P = 0.005), and similar OS (P = 0.656) than LVSI absent group for endometrioid EC patients. For non-endometrioid EC patients, there was no statistical difference in either DFS (P = 0.536) or OS (P = 0.512) after matching. The multivariate Cox analysis showed that LVSI was an independent risk factor of DFS [hazard ratio (HR) 2.62, 95% confidence intervals (CI) 1.35-5.10, P = 0.005] and not OS (HR 1.24, 95%CI 0.49-3.13, P = 0.656) for endometrioid EC patients. It was not a prognostic factor of either DFS (HR 1.28, 95%CI 0.58-2.81, P = 0.539) or OS (HR 1.33, 95%CI 0.55-3.13, P = 0.515) for non-endometrioid EC patients. CONCLUSION: LVSI is an adverse prognostic factor for endometrioid EC patients and has no impact on non-endometrioid EC patients. Necessity of postoperative adjuvant therapy based on LVSI needs to be carefully considered for non-endometrioid EC patients.

Prognostic significance of omental disease and the role of omentectomy in non-endometrioid endometrial cancer.

OBJECTIVES: Non-endometrioid endometrial cancers (non-EEC) have different management from endometrioid endometrial cancers. The purpose of this study was to investigate the prognostic significance of omental disease and the role of omentectomy in non-endometrioid endometrial cancer and discuss the current literature with the findings. MATERIAL AND METHODS: The study included two hundred-three patients with non-EEC who underwent surgical treatment and follow-up between January 1996 and December 2018 in a University Hospital Gynecologic Oncology Center. The patients were divided into three groups according to whether omentectomy was performed and the presence of omental metastasis. The patient's demographics, clinical characteristics such as stage, grade, histopathologic type, lymphovascular space invasion (LVSI), myometrial invasion, lymph node involvement, and survival outcomes were compared between the groups. RESULTS: The study included 203 patients. Twenty-five patients (12%) had omental metastases. LVSI was reported in 57.3%, 88.0%, and 43.2% of the non-omentectomy, no-omental metastasis, and omental metastatic groups, respectively (p = 0.001). The 5-year disease-free survival (DFS) and overall survival (OS) rates according to the tumor grade, peritoneal cytology, and lymphadenectomy were also compared and were found to be statistically similar. The five-year OS rates were 70.6% for the group without omental metastases and 16.2% for the group with omental metastases, respectively (p = 0.001). In the group of omentectomy, the five-year DFS rates were 62.2% in cases without omental metastasis and 13.0% in cases with omental metastasis (p = 0.001). The five-year OS rates of 86.3% and DFS rates of 80.0% in the group without omentectomy. CONCLUSIONS: In non-endometrioid tumors, the survival rate was better in the group that did not undergo omentectomy. Based on these results, we can say that omentectomy may not be necessary for non-endometrioid tumors whose omentum is found to be normal in intraoperative visual examination.

Microbial Communities in Gynecological Cancers and Their Association with Tumor Somatic Variation.

There are strong correlations between the microbiome and human disease, including cancer. However, very little is known about potential mechanisms associated with malignant transformation in microbiome-associated gynecological cancer, except for HPV-induced cervical cancer. Our hypothesis is that differences in bacterial communities in upper genital tract epithelium may lead to selection of specific genomic variation at the cellular level of these tissues that may predispose to their malignant transformation. We first assessed differences in the taxonomic composition of microbial communities and genomic variation between gynecologic cancers and normal samples. Then, we performed a correlation analysis to assess whether differences in microbial communities selected for specific single nucleotide variation (SNV) between normal and gynecological cancers. We validated these results in independent datasets. This is a retrospective nested case-control study that used clinical and genomic information to perform all analyses. Our present study confirms a changing landscape in microbial communities as we progress into the upper genital tract, with more diversity in lower levels of the tract. Some of the different genomic variations between cancer and controls strongly correlated with the changing microbial communities. Pathway analyses including these correlated genes may help understand the basis for how changing bacterial landscapes may lead to these cancers. However, one of the most important implications of our findings is the possibility of cancer prevention in women at risk by detecting altered bacterial communities in the upper genital tract epithelium.

The Prognostic Characteristics and Recurrence Patterns of High Grade Endometrioid Endometrial Cancer: A Large Retrospective Analysis of a Tertiary Center.

High grade endometrioid endometrial cancer (HGEEC) is a heterogeneous group of tumors with unclear prognostic features. The aim of the present study is to evaluate the independent risk factors for recurrence and mortality and to describe the recurrence patterns of HGEEC. Ninety-six consecutive cases of HGEEC treated with primary surgery in a single Tertiary Center were retrospectively reviewed. Clinicopathological and treatment details were recorded, and all patients were closely followed up. Disease-free, overall and cancer-specific survival rates were 83.8%, 77.8% and 83.6%, respectively. Cervical stromal involvement was independently related to recurrence (HR = 25.67; 95%CI 2.95-223.30; p = 0.003) and cancer-related death (HR = 15.39; 95%CI 1.29-183.43; p = 0.031) after adjusting for other pathological and treatment variables. Recurrence rate was 16%, with 60% of these cases having lung metastases and only one case with single vaginal vault recurrence. 81.81% of the recurrences presented with symptoms and not a single recurrence was diagnosed in routine follow-up clinical examination. In conclusion, the recurrence pattern may suggest that patient-initiated follow-up (PIFU) could be considered a potential alternative to clinical-based follow-up for HGEEC survivors, especially for patients without cervical involvement and after two years from treatment. Additional caution is needed in patients with cervical stromal involvement.

A miRNA-205-based model for prediction of the recurrence of endometrioid endometrial cancer.

AIM: To develop a miRNA-205 based model for prediction of the recurrence of endometrial cancer. METHODS: The FIGO (International Federation of Gynecology and Obstetrics) stage, grading, myometrial infiltration, lymph node status and miRNA-205 expression levels were extracted from 90 endometrioid endometrial cancer patients, recurrence related risk factors were analyzed by Cox regression analysis. A risk model was then developed. RESULTS: A total of 90 endometrial cancer patients were retrospectively included for the analysis. The FIGO stage and expression levels of miRNA 205 were independently associated with the recurrence-free survival of the patients. The FIGO stage and expression levels of miRNA 205 were used for a prognostic model of recurrence-free survival. The c-index of the model reached 0.764, and the output of the model (risk score) could stratify the patients into different groups on the risk of recurrence. CONCLUSION: A miRNA-205 based model could predict the risk of recurrence for endometrioid endometrial cancer, and the model could provide a risk stratification of patients by recurrence risk.

HER2+ endometrioid endometrial cancer possesses distinct molecular and immunologic features associated with a more active immune microenvironment and worse prognosis.

OBJECTIVE: HER2 status is not routinely evaluated in endometrioid endometrial cancer (E-EMCA), though it is frequently overexpressed or amplified in high grade E-EMCA and uterine serous carcinoma. Defining characteristics and survival outcomes of HER2+ E-EMCA could reveal subsets of patients who may benefit from targeted therapies. METHODS: 2927 E-EMCA tumors from the Caris Life Sciences database were analyzed by next-generation sequencing and whole exome sequencing, whole transcriptome sequencing, and immunohistochemistry for molecular and genomic features in a CLIA/CAP-certified laboratory (Caris Life Sciences, Phoenix, AZ). HER2 status was determined by transcriptomic cutoff extrapolated from uterine serous carcinoma. The relationship between HER2 status and patient outcomes was determined by Kaplan-Meier analysis. RESULTS: HER2 positivity was detected in 5.47% of E-EMCA. Differences in molecular alterations based on HER2 status were most apparent in microsatellite stable (MSS) tumors, which displayed increased TP53 mutations and loss of heterozygosity (LOH) and decreased PTEN and CTNNB1 mutations. HER2+ tumors had increased immune checkpoint gene expression and immune cell infiltration, particularly among MSS tumors. All HER2+ tumors displayed increased MAPK pathway activation scores (MPAS) and patients with HER2+ tumors experienced worse overall survival. CONCLUSIONS: HER2 positivity in E-EMCA corresponds with a unique molecular landscape, particularly in MSS tumors. HER2+ tumors are also associated with increased MAPK pathway activation and exhibit features of a more active immune microenvironment. These findings suggest a potential benefit of HER2 and MAPK targeted therapies as well as immunotherapies in this patient population.

LncRNA HOXB-AS3 binding to PTBP1 protein regulates lipid metabolism by targeting SREBP1 in endometrioid carcinoma.

Endometrial cancer (EC) is a malignant tumor with a high incidence in women, and the survival rate of high-risk patients decreases significantly after disease progression. The regulatory role of long non-coding RNAs (LncRNAs) in tumors has been widely appreciated, but there have been few studies in EC. To investigate the effect of HOXB-AS3 in EC, we used bioinformatics tools for prediction and collected clinical samples to detect the expression of HOXB-AS3. Colony formation assay, MTT assay, flow cytometry and apoptosis assay, and transwell assay were used to verify the role of HOXB-AS3 in EC. HOXB-AS3 was upregulated in EC, promoted the proliferation and invasive ability of EC cells, and inhibited apoptosis. In addition, the ROC curve illustrated its diagnostic value. We explored experiments via lentiviral transduction, FISH, Oil Red O staining, TC and FFA content detection, RNA-pulldown, RIP, and other mechanisms to reveal that HOXB-AS3 can bind to PTBP1 and co-regulate the expression of SREBP1, thereby regulating lipid metabolism in EC cells. To the best of our knowledge, this is the first study on HOXB-AS3 in disorders of lipid metabolism in EC. In addition, we believe HOXB-AS3 has the potential to be a neoplastic marker or a therapeutic target.

The expression of stanniocalcin-1, estrogen receptor and progesterone receptor in endometrioid endometrial cancer.

Objective: To evaluate the expression of stanniocalcin-1 (STC-1) and to investigate the correlation of STC-1 with expression of estrogen receptor (ER), progesterone receptor (PR) and clinical parameters, histopathological findings and prognostic factors in endometrioid endometrial cancer (EEC). Materials and Methods: In this retrospective study, STC-1 (cytoplasmic), ER (nuclear), and PR (nuclear) stainings were applied to tissue microarray sections of 89 EEC, 27 endometrial intraepithelial neoplasia (EIN), and 21 normal endometrium (NE). Prognostic factors such as age, tumor size, depth of myometrial invasion, lymphovascular invasion, perineural invasion, and lymph node metastasis were compared with the expression of these markers. Results: ER showed significantly higher positivity in grade 1 EEC. PR expression was also higher in grade 1 EEC, but these findings were not statistically significant. Strong expression of STC-1 was observed in EIN and EECs compared with NE. STC-1 showed low staining in the NE, and high staining was also noted in the EIN foci adjacent to the NE. STC-1 expression was positively correlated with grade 1 EECs. Conclusion: STC-1 expression was positively correlated with low histologic grade in EECs. STC-1 can be used for distinguishing low-grade endometrioid tumors and high -grade endometrioid tumors in curretage specimens. Since STC-1 is related to well differentiated tumors, it can also be regarded as a good prognostic factor in EECs.

Detection and Genotyping of Human Papillomavirus (HPV16/18), Epstein-Barr Virus (EBV), and Human Cytomegalovirus (HCMV) in Endometrial Endometroid and Ovarian Cancers.

The purpose of this study was to evaluate the relationship between human papillomavirus (HPV16/18), Epstein-Barr virus (EBV), and human cytomegalovirus (HCMV) infections and the occurrence of ovarian cancer in 48 women, of whom 36 underwent surgery and chemotherapy (group A), 12 in whom surgery was sufficient (group B), and 60 with endometroid endometrial cancer stage G1-G3 (group C), compared to patients in whom the uterus and its appendages were removed for nononcological reasons (control group). The detection of HPV, EBV, and HCMV in tumor tissue and normal tissue was performed using the real-time polymerase chain reaction (RT-PCR) technique. A statistically significantly higher risk of endometrial cancer was noted in patients infected only with HCMV (OR > 1; p < 0.05). In contrast, a significantly higher risk of ovarian cancer in group A was associated with HPV16, HPV18, and EBV (OR > 1; p < 0.05); a significantly higher risk of ovarian cancer in group B was associated with HPV18 and HMCV (OR > 1; p < 0.05). The obtained results suggest that HCMV infection is associated with the development of a stage of ovarian cancer when treatment can be completed with surgery alone. Meanwhile, EBV appears to be responsible for the development of ovarian cancer in more advanced stages.

Shared sex hormone metabolism-related gene prognostic index between breast and endometrial cancers.

Aims: As sex hormone-dependent tumors, it remains to be clarified whether there is a common genetic signature and its value between breast and endometrial cancers. The aim of this study was to establish the shared sex hormone metabolism-related gene prognostic index (SHMRGPI) between breast and endometrial cancers and to analyze its potential role in the therapeutic and prognostic assessment of endometrial cancers. Methods: Using transcriptome data from TCGA, tumor-associated gene modules were identified by weighted gene co-expression network analysis, and the intersection of module genes with female sex hormone synthesis and metabolism genes was defined as sex hormone metabolism-related gene. SHMRGPI was established by the least absolute shrinkage and selection operator and Cox regression. Its prognostic value of patients with endometrial cancer was validated, and a nomogram was constructed. We further investigated the relationship between SHMRGPI groups and clinicopathological features, immune infiltration, tumor mutation burden, and drug sensitivity. Results: A total of 8 sex hormone metabolism-related gene were identified as key genes for the construction of prognostic models. Based on SHMRGPI, endometrial cancer patients were divided into high and low SHMRGPI groups. Patients in the low SHMRGPI group had longer overall survival (OS) compared with the high group (P< 0.05). Furthermore, we revealed significant differences between SHMRGPI groups as regards tumor immune cell infiltration, somatic mutation, microsatellite instability and drug sensitivity. Patients with low SHMRGPI may be the beneficiaries of immunotherapy and targeted therapy. Conclusions: The SHMRGPI established in this study has prognostic power and may be used to screen patients with endometrial cancer who may benefit from immunotherapy or targeted therapy.

Exploitation of a shared genetic signature between obesity and endometrioid endometrial cancer.

Aims: The findings in epidemiological studies suggest that endometrioid endometrial cancer (EEC) is associated with obesity. However, evidence from gene expression data for the relationship between the two is still lacking. The purpose of this study was to explore the merits of establishing an obesity-related genes (ORGs) signature in the treatment and the prognostic assessment of EEC. Methods: Microarray data from GSE112307 were utilized to identify ORGs by using weighted gene co-expression network analysis. Based on the sequencing data from TCGA, we established the prognostic ORGs signature, confirmed its value as an independent risk factor, and constructed a nomogram. We further investigated the association between grouping based on ORGs signature and clinicopathological characteristics, immune infiltration, tumor mutation burden and drug sensitivity. Results: A total of 10 ORGs were identified as key genes for the construction of the signature. According to the ORGs score computed from the signature, EEC patients were divided into high and low-scoring groups. Overall survival (OS) was shorter in EEC patients in the high-scoring group compared with the low-scoring group (P < 0.001). The results of the Cox regression analysis showed that ORGs score was an independent risk factor for OS in EEC patients (HR = 1.017, 95% confidence interval = 1.011-1.023; P < 0.001). We further revealed significant disparities between scoring groups in terms of clinical characteristics, tumor immune cell infiltration, and tumor mutation burden. Patients in the low-scoring group may be potential beneficiaries of immunotherapy and targeted therapies. Conclusions: The ORGs signature established in this study has promising prognostic predictive power and may be a useful tool for the selection of EEC patients who benefit from immunotherapy and targeted therapies.

Microsatellite instability as a marker of prognosis: a systematic review and meta-analysis of endometrioid endometrial cancer survival data.

INTRODUCTION: To investigate whether microsatellite instability (MSI) is an important prognostic biomarker for endometrioid endometrial cancer (EEC). METHODS: The PubMed, EMBASE, and the Cochrane Cooperative Library databases were searched from inception to July 2021. Overall survival, disease-free survival, progression-free survival, EEC-specific survival, recurrence-free survival, and the recurrence rate were pooled to analyze the correlation between MSI and EEC. In addition, Egger's regression analysis and Begg's test were used to detect publication bias. RESULTS: 17 studies met the inclusion criteria and were included in our meta-analysis with a sample size of 4723, and the included patients with endometrioid cancer (EC) all were EEC. The pooled hazard ratios (HR) in patients with EEC showed that MSI was significantly associated with shorter overall survival [HR = 1.37, 95% confidence interval (CI) (1.00-1.86), p = 0.048, I2 = 60.6%], shorter disease-free survival [HR = 1.99, 95% CI (1.31-3.01), p = 0.000, I2 = 67.2%], shorter EEC-specific survival [HR = 2.07, 95% CI (1.35-3.18), p = 0.001, I2 = 31.6%] and a higher recurrence rate [Odds ratios (OR) = 2.72, 95% CI (1.56-4.76), p = 0.000, I2 = 0.0%]. In the early-stage EEC subgroup, MSI was significantly associated with shorter overall survival [HR = 1.47, 95% CI (1.11-1.95), p = 0.07], shorter disease-free survival [HR = 4.17, 95% CI (2.37-7.41), p = 0.000], and shorter progression-free survival [HR = 2.41, 95% CI (1.05-5.54), p = 0.039]. No significant heterogeneity was observed in overall survival (I2 = 20.9%), disease-free survival (I2 = 0.0%), or progression-free survival (I2 = 0.0%) in patients with early-stage EEC. Meanwhile, publication bias was not observed, and the p-value for Egger's test of overall survival, disease-free survival, and EEC-specific survival were p = 0.131, p = 0.068, and p = 0.987, respectively. CONCLUSION: MSI is likely an important biomarker for poor prognosis in patients with EEC, and this correlation is even more certain in patients with early-stage EEC.

Promoter methylation status of key genes and its implications in the pathogenesis of endometriosis, endometrioid carcinoma of ovary and endometrioid endometrial cancer.

Background: Epigenetic processes play an important role in various physiological processes as well as in the pathogenesis of many diseases. The role of altered DNA methylation in the pathogenesis of endometriosis and associated ovarian and endometrial cancers has not been explored in detail. Therefore, this study aimed to determine the promoter methylation status of genes involved in key biological processes in the pathogenesis of these three gynecological diseases. Methods: Tissue samples of endometriosis, endometrioid carcinoma of the ovary, endometrioid endometrial cancer, and control endometrium (n = 10 each) were obtained. DNA was extracted and subjected to bisulfite conversion using commercially available kits. The methylation status of COX2, VEGF, HIF1A, TNF, MYC, and TP53 genes was checked by methylation-specific PCR. The mRNA levels of MYC and TP53 were determined using qRT-PCR in all tissue samples. Results: The promoter methylation status of COX2, VEGF, HIF1A, and TNF genes was significantly reduced in all three diseased study subjects (P < 0.05), whereas no significant difference was observed in the promoter methylation frequency of MYC and TP53 genes. Transcriptional expression of the MYC gene was significantly increased in all diseased groups (P < 0.001) whereas, transcriptional expression of the TP53 gene was significantly reduced in endometriosis and endometrioid carcinoma of the ovary and significantly increased in endometrioid endometrial cancer subjects compared to control subjects (P < 0.001). Conclusion: The findings suggest that the promoter regions of pro-inflammatory and pro-angiogenic genes involved in the common molecular pathophysiology of these three disorders were significantly hypomethylated and could be the reason for their over-expression associated with them. This indicates the role of epigenetics in the pathogenesis of these three diseases.