BACKGROUND: Observational research has reported that systemic lupus erythematosus (SLE) is related to common female hormone-dependent cancers, but the underlying causal effect remains undefined. This study aimed to explore the causal association of these conditions by Mendelian randomization (MR) analysis. METHODS: We selected instrumental variables for SLE from genome-wide association studies (GWASs) conducted in European and East Asian populations. The genetic variants for female malignant neoplasms were obtained from corresponding ancestry GWASs. We utilized inverse variance weighted (IVW) as the primary analysis, followed by sensitivity analysis. Furthermore, we conducted multivariable MR (MVMR) to estimate direct effects by adjusting for the body mass index and estradiol. Finally, we implemented reverse direction MR analysis and gave a negative example to test the reliability of MR results. RESULTS: We found SLE was significantly negatively associated with overall endometrial cancer risk (odds ratio [OR] = 0.961, 95% confidence interval [CI] = 0.935-0.987, P  = 3.57E-03) and moderately inversely related to endometrioid endometrial cancer (ENEC) (OR = 0.965, 95% CI = 0.936-0.995, P  = 0.024) risk in the European population by IVW. We replicated these results using other MR models and detected a direct effect by MVMR (overall endometrial cancer, OR = 0.962, 95% CI = 0.941-0.983, P  = 5.11E-04; ENEC, OR = 0.964, 95% CI = 0.940-0.989, P  = 0.005). Moreover, we revealed that SLE was correlated with decreased breast cancer risk (OR = 0.951, 95% CI = 0.918-0.986, P  = 0.006) in the East Asian population by IVW, and the effect was still significant in MVMR (OR = 0.934, 95% CI = 0.859-0.976, P  = 0.002). The statistical powers of positive MR results were all >0.9. CONCLUSION This finding suggests a possible causal effect of SLE on the risk of overall endometrial cancer and breast cancer in European and East Asian populations, respectively, by MR analysis, which compensates for inherent limitations of observational research.
Female ; Humans ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; Neoplasms, Hormone-Dependent ; Reproducibility of Results ; Endometrial Neoplasms ; Lupus Erythematosus, Systemic/genetics* ; Carcinoma, Endometrioid ; Breast Neoplasms ; Polymorphism, Single Nucleotide

Objective: To investigate the molecular classification and clinicopathological features of endometrial carcinoma(EC). Methods: One hundred cases of EC diagnosed in the Department of Pathology, Tianjin Central Hospital of Gynecology and Obstetrics from November 2020 to November 2021 were selected. Sanger sequencing and immunohistochemical staining were used for molecular classification according to the 5th WHO classification. The clinicopathological characteristics of each molecular subtype was analyzed. Results: The 100 EC patients had a mean age of 53 years (range 26 to 72 years). There were 10 cases of POLE mutation (POLE mut), including two cases (2/10) of "binary-classifier" EC, two cases (2/10) of FIGO Grade 3 endometrioid endometrial carcinoma (G3-EEC), and three cases (3/10) of other high-grade subtypes. There were 38 cases of mismatch repair deficiency (dMMR), including one case (1/38, 2.6%) of "binary-classifier" EC and 36 cases (36/38, 94.7%) were EEC. Twenty-one cases (21/38, 55.3%) showed simultaneous loss of expression of MLH1 and PMS2, and 20 cases (20/21, 95.2%) were positive for MLH1 methylation, indicating that they were sporadic EC. Six patients (6/38, 15.8%) were tested for germline detection of Lynch syndrome (LS) related genes, and one patient was LS-related EC. There were 44 cases of non-specific molecular profile (NSMP), including 34 cases (34/44, 77.3%) of G1-2 EEC and seven cases (7/44, 15.9%) of G3-EEC. There were eight cases of p53 abnormality (p53 abn), including four cases (4/8) of G3-EEC, two cases (2/8) of other high-grade subtypes, and one patient had hereditary breast cancer and ovarian cancer syndrome. Conclusions: Correct interpretation of POLE mutation, MMR and p53 immunohistochemistry is the key of molecular classification. The interpretation must strictly follow standard diagnostic procedures and specifications to ensure the accuracy of molecular classification.
Adult ; Aged ; Carcinoma, Endometrioid/genetics* ; Colorectal Neoplasms, Hereditary Nonpolyposis/pathology* ; DNA Mismatch Repair ; Endometrial Neoplasms/pathology* ; Female ; Humans ; Middle Aged ; Mismatch Repair Endonuclease PMS2/metabolism* ; MutL Protein Homolog 1/metabolism* ; Tumor Suppressor Protein p53/metabolism*

BACKGROUND: DNA methylation is involved in numerous biologic events and associates with transcriptional gene silencing, playing an important role in the pathogenesis of endometrial cancer. ESR1/PGR frequently undergoes de novo methylation and loss expression in a wide variety of tumors, including breast, colon, lung, and brain tumors. However, the mechanisms underlying estrogen and progesterone receptors (ER/PR) loss in endometrial cancer have not been studied extensively. The aims of this study were to determine the expression of DNA (cytosine-5)-methyltransferase 3A/3B (DNMT3A/3B) in endometrial cancer to investigate whether the methylation catalyzed by DNMT3A/3B contributes to low ER/PR expression. METHODS: The clinicopathologic information and RNA-Seq expression data of DNMT3A/3B of 544 endometrial cancers were derived from The Cancer Genome Atlas (TCGA) uterine cancer cohort in May 2018. RNA-Seq level of DNMT3A/3B was compared between these clinicopathologic factors with t-test or one-way analysis of variance. RESULTS: DNMT3A/3B was overexpressed in endometrioid carcinoma (EEC) and was even higher in non-endometrioid carcinoma (NEEC) (DNMT3A, EEC vs. NEEC: 37.6% vs. 69.9%, t = -7.440, P < 0.001; DNMT3B, EEC vs. NEEC: 42.4% vs. 72.8%, t = -6.897, P < 0.001). In EEC, DNMT3A overexpression was significantly correlated with the hypermethylation and low expression of the ESR1 and PGR (P < 0.05). The same trend was observed in the DNMT3B overexpression subgroup. In the ESR1/PGR low-expression subgroups, as much as 83.1% of ESR1 and 59.5% of PGR were hypermethylated, which was significantly greater than the ESR1/PGR high-expression subgroups (31.3% and 11.9%, respectively). However, the above phenomena were absent in NEEC, while DNMT3A/3B overexpression, ESR1/PGR hypermethylation, and low ER/PR expression occurred much more often. In univariate analysis, DNMT3A/3B overexpressions were significantly correlated with worse prognosis. In multivariate analysis, only DNMT3A was an independent predictor of disease-free survival (P < 0.05). CONCLUSIONS DNMT3A/3B expression increases progressively from EEC to NEEC and is correlated with poor survival. The mechanisms underlying low ER/PR expression might be distinct in EEC vs. NEEC. In EEC, methylation related to DNMT3A/3B overexpression might play a major role in ER/PR downregulation.
Adult ; Aged ; Aged, 80 and over ; Carcinoma, Endometrioid ; genetics ; metabolism ; pathology ; DNA (Cytosine-5-)-Methyltransferases ; genetics ; metabolism ; DNA Methylation ; genetics ; Endometrial Neoplasms ; genetics ; metabolism ; pathology ; Estrogen Receptor alpha ; genetics ; metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Prognosis

BACKGROUNDPreviously, we reported that dual-specificity phosphatase 1 (DUSP1) was differentially expressed in endometrioid adenocarcinoma (EEA). However, the role of DUSP1 in EEA progression and the relationship between DUSP1 and medroxyprogesterone (MPA) are still unclear.

METHODSThe expression of DUSP1 in EEA specimens was detected by immunohistochemical analysis. The effect of DUSP1 on cell proliferation was analyzed by Cell Counting Kit 8 and colony formation assay, and cell migration was analyzed by transwell assay. MPA-induced DUSP1 expression in EEA cells was measured by Western blot.

RESULTSDUSP1 expression was deficient in advanced International Federation of Gynecology and Obstetrics stage, high-grade and myometrial invasive EEA. In EEA cell lines (Hec1A, Hec1B, RL952, and Ishikawa), the DUSP1 expression was substantially higher in Ishikawa cells than in other cell lines (P < 0.05). Knockdown of DUSP1 promoted Ishikawa cells proliferation, migration, and activation of mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/Erk) pathway. MPA-induced DUSP1 expression and inhibited MAPK/Erk pathway in Ishikawa cells.

CONCLUSIONSOur data suggest that DUSP1 deficiency promotes EEA progression via MAPK/Erk pathway, which may be reversed by MPA, suggesting that DUSP1 may serve as a potential therapeutic target for the treatment of EEA.

Carcinoma, Endometrioid ; metabolism ; Cell Culture Techniques ; Cell Proliferation ; genetics ; physiology ; Dual-Specificity Phosphatases ; genetics ; metabolism ; Extracellular Signal-Regulated MAP Kinases ; metabolism ; Female ; Humans ; Mitogen-Activated Protein Kinases ; metabolism

Ovarian tumors comprise a heterogeneous group of lesions, displaying distinct tumor pathology and oncogenic potentiel. These tumors are subdivided into three main categories: epithelial, germ cell, and sex-cord stromal tumors. We report herein the newly described molecular abnormalities in epithelial ovarian cancers (carcinomas). Immunohistochemistry and molecular testing help pathologists to decipher the significant heterogeneity of this disease. Our better understanding of the molecular basis of ovarian carcinomas represents the first step in the development of targeted therapies in the near future.
Carcinoma, Endometrioid ; pathology ; Cystadenocarcinoma, Mucinous ; pathology ; Cystadenocarcinoma, Serous ; pathology ; Female ; Humans ; Mixed Tumor, Malignant ; pathology ; Neoplasms, Glandular and Epithelial ; pathology ; Ovarian Neoplasms ; genetics ; pathology

OBJECTIVETo study the diagnostic value of HNF-1β and Napsin A for ovarian clear cell carcinomas, serous carcinomas, endometrioid adenocarcinomas and metastatic Krukenberg tumors.

METHODSImmunohistochemical EnVision method was used to detect the expression of HNF-1β and Napsin A in 38 cases of ovarian clear cell carcinoma, 30 cases of high-grade serous carcinoma, 22 cases of endometrioid adenocarcinoma and 16 cases of metastatic Krukenberg tumor. Expression of HNF-1β and Napsin A were compared, and sensitivity and specificity of clear cell carcinoma of the ovary were analysed.

RESULTSThe positive rate of HNF-1β in the ovarian clear cell carcinoma was 100%(38/38), higher than those in high-grade serous carcinoma and endometrioid adenocarcinoma (P<0.05), although significant difference was not observed from that of metastatic Krukenberg tumor (P>0.05). Napsin A expressed in 97.4% (37/38) of ovarian clear cell carcinoma, 6.7% (2/30) of high-grade serous carcinoma, 22.7% (5/22) of endometrioid adenocarcinoma. Napsin A expression in clear cell carcinoma was higher than those in high-grade serous carcinoma and endometrioid adenocarcinoma (P<0.01), and no expression of Napsin A was seen in metastatic Krukenberg tumor (P>0.05). The sensitivity and specificity of HNF-1β in the diagnosis of ovarian clear cell carcinoma were 100% and 52.9%, those of Napsin A were 97.4% and 91.2%, those of both HNF-1β and Napsin A were 97.4% and 91.2%, respectively. The sensitivity and specificity of HNF-1β or Napsin A in the diagnosis of ovarian clear cell carcinoma were 100% and 52.9%, respectively.

CONCLUSIONSHNF-1β is a more sensitive marker for the diagnosis of ovarian clear cell carcinoma, whereas Napsin A is a more specific marker. The combined detection of HNF-1β and Napsin A may be helpful for the diagnosis of clear cell carcinoma of the ovary.

Adenocarcinoma, Clear Cell ; diagnosis ; Aspartic Acid Endopeptidases ; genetics ; Biomarkers, Tumor ; genetics ; Carcinoma, Endometrioid ; diagnosis ; Cystadenocarcinoma, Serous ; diagnosis ; Female ; Hepatocyte Nuclear Factor 1-alpha ; genetics ; Humans ; Immunohistochemistry ; Krukenberg Tumor ; diagnosis ; Ovarian Neoplasms ; diagnosis ; Sensitivity and Specificity

OBJECTIVETo determine the microRNA (miRNA) expression signature and its clinical significance in endometrioid carcinoma (EC).

METHODSThe miRNA profiles were analyzed by miRNA microarray in 73 cases of EC. The expression level of the eight selected miRNAs were measured by real-time fluorescent quatitative PCR(qRT-PCR). Immunohistochemistry (IHC) was performed to assess the status of PTEN, a potential target of the selected miRNAs.

RESULTS(1) Using TaqMan low-density arrays, 47 miRNAs that differed between EC and normal controls were identified, including 26 down-regulated and 21 up-regulated miRNAs. (2) To confirm the miRNA expression pattern in typeIEC, the expression levels of the eight selected miRNAs were evaluated in a new set of 58 cases of typeIEC by individual miRNA qRT-PCR assays. Three miRNAs (miR-141, miR-200a, miR-205) were up-regulated and two miRNAs (miR-143, miR-145) were down-regulated. These were significantly differentially expressed in typeIEC and normal controls (P < 0.05), whereas such difference was not present in type II tumors compared to normal controls. (3) In typeIEC, loss of PTEN was more frequent in the miR-141 or miR-200a up-regulated subgroups, and the correlation between the PTEN and miR-200a status in typeItumors was statistically significant (P < 0.05).

CONCLUSIONSEC may have a unique miRNA expression profile. The expression levels of the five miRNAs (miR-141, miR-200a, miR-205, miR-143, miR-145) are significantly deregulated in typeIEC compared to normal control but not in typeIItumors. The findings suggest that the miRNAs related to type Iand typeIIEC might be different. PTEN might be a potential target of miR-141 and miR-200a in endometrial carcinogenesis.

Adenocarcinoma, Clear Cell ; genetics ; Adenocarcinoma, Mucinous ; genetics ; Adult ; Aged ; Carcinoma, Endometrioid ; genetics ; Endometrial Neoplasms ; classification ; genetics ; Endometrium ; metabolism ; Female ; Follow-Up Studies ; Gene Expression Profiling ; Humans ; Lymphatic Metastasis ; MicroRNAs ; metabolism ; Middle Aged ; Neoplasm Staging ; PTEN Phosphohydrolase ; metabolism ; Survival Rate

Adaptor Proteins, Signal Transducing ; metabolism ; Adenocarcinoma, Clear Cell ; genetics ; metabolism ; pathology ; surgery ; Adenosine Triphosphatases ; metabolism ; Age Factors ; Carcinoma, Endometrioid ; genetics ; metabolism ; pathology ; surgery ; Colorectal Neoplasms, Hereditary Nonpolyposis ; genetics ; metabolism ; pathology ; surgery ; Cystadenocarcinoma, Serous ; genetics ; metabolism ; pathology ; surgery ; DNA Mismatch Repair ; DNA Repair Enzymes ; metabolism ; DNA-Binding Proteins ; metabolism ; Endometrial Neoplasms ; genetics ; metabolism ; pathology ; surgery ; Female ; Humans ; Mismatch Repair Endonuclease PMS2 ; MutL Protein Homolog 1 ; MutS Homolog 2 Protein ; metabolism ; Neoplasms, Multiple Primary ; genetics ; metabolism ; pathology ; surgery ; Nuclear Proteins ; metabolism

OBJECTIVETo investigate apoptosis of tumor infiltrating dendritic cells (TIDC) and their expression of Fas/FasL (CD95/CD95L) in human endometrioid adenocarcinoma.

METHODSThe apoptotic rate of TIDC was measured in 45 cases of endometrioid adenocarcinoma and 20 cases of normal endometrium tissues (control) by double-label immunohistochemistry using the monoclonal antibody S-100 protein and TUNEL technique. The expressions of Fas and FasL in TIDCs were detected using double-label immunohistochemistry and imaging analysis.

RESULTSThe apoptotic rate of TIDCs in endometrioid adenocarcinoma were significantly higher than that in normal endormetrium [(13.02∓0.64)% vs (6.82∓0.53)%, P<0.05]. The expression levels of Fas in the TIDCs were significantly lower, whereas FasL expression significantly higher in endometrioid adenocarcinoma than in normal endormetrium (7.88∓1.05 vs 19.25∓3.03, P<0.05; 12.95∓2.25 vs 7.51∓1.14, P<0.05).

CONCLUSIONIncreased apoptosis of the TIDCs and abnormal expression of Fas/FasL in TIDCs in endometrioid adenocarcinoma may lead to tumor immune escape.

Apoptosis ; physiology ; Carcinoma, Endometrioid ; immunology ; metabolism ; pathology ; Case-Control Studies ; Dendritic Cells ; immunology ; Endometrial Neoplasms ; immunology ; metabolism ; pathology ; Fas Ligand Protein ; genetics ; metabolism ; Female ; Humans ; Lymphocytes, Tumor-Infiltrating ; immunology ; Tumor Escape ; fas Receptor ; genetics ; metabolism

OBJECTIVETo investigate the clinicopathologic and prognostic implications of phosphoinositide 3 kinase (PI3K)/AKT pathway alterations in endometrial cancers of Chinese women.

METHODSThe expression of PTEN, p-AKT, and ER/PR was assessed in 71 cases of endometrial carcinoma by immunohistochemistry (EnVision method). The PIK3CA mutation at exon 9 and exon 20 was analyzed by PCR and direct sequencing in 34 tumors.

RESULTS(1) Of the 71 cases of endometrial carcinoma, 65 cases were endometrioid adenocarcinoma (EEC) and 6 cases were nonendometrioid adenocarcinoma (NEEC). PTEN loss of expression was found in 63.4% (45/71) of tumors, and more commonly occurred in EEC (66.2%, 43/65) than that in NEEC (2/6, P = 0.18). Patients with PTEN loss in their tumors (45 cases) had a better survival than those without (26 cases, P = 0.07). In ER negative subgroup, the patients with PTEN loss of expression (12 cases) had longer survival than those with normal PTEN expression (7 cases; P = 0.04). (2) The frequency of PIK3CA mutation was 41.2% (14/34) with a hot mutation spot at T544 in exon 9. PIK3CA mutations more commonly occurred in EEC (44.8%, 13/29) than in NEEC (1/5, P > 0.05). The mutations at exon 9 more commonly occurred in EEC, well- and moderately-differentiated EEC, and tumors at early stage (P > 0.05). On the contrary, in tumors at early stages, the frequency of mutations in exon 20 (14.3%, 4/28) was significantly lower than that at late stages (4/6, P = 0.01). (3) p-AKT was positive in 59.2% (42/71) of tumors that were more frequently found in EEC (60.0%, 39/65) than that in NEEC (3/6, P = 0.68). However, the significant difference of p-AKT expression was found between well- and moderately-differentiated EEC (75.0%, 21/28; 53.6%, 15/28) and poorly-differentiated EEC (3/9, P = 0.02). Moreover, p-AKT expression was significantly correlated with positive ER (r = 0.339, P = 0.00).

CONCLUSIONSEndometrial carcinoma patients with loss of PTEN and p-AKT positivity have a favorable prognosis. PIK3CA mutations at exon 9 or 20 may have different impact on the prognosis. The function of PTEN loss and p-AKT expression may vary according to different hormone status.

Adult ; Aged ; Carcinoma, Endometrioid ; genetics ; metabolism ; pathology ; surgery ; Class I Phosphatidylinositol 3-Kinases ; Endometrial Neoplasms ; genetics ; metabolism ; pathology ; surgery ; Exons ; Female ; Follow-Up Studies ; Humans ; Hysterectomy ; Middle Aged ; Mutation ; Neoplasm Invasiveness ; Neoplasm Staging ; PTEN Phosphohydrolase ; metabolism ; Phosphatidylinositol 3-Kinases ; genetics ; metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt ; metabolism ; Receptors, Estrogen ; metabolism ; Receptors, Progesterone ; metabolism ; Signal Transduction ; Survival Rate