Impact of genomic stability on protein expression in endometrioid endometrial cancer.
Ontology highlight
ABSTRACT: Background
Genomic stability is one of the crucial prognostic factors for patients with endometrioid endometrial cancer (EEC). The impact of genomic stability on the tumour tissue proteome of EEC is not yet well established.Methods
Tissue lysates of EEC, squamous cervical cancer (SCC), normal endometrium and squamous cervical epithelium were subjected to two-dimensional (2D) gel electrophoresis and identification of proteins by MALDI TOF MS. Expression of selected proteins was analysed in independent samples by immunohistochemistry.Results
Diploid and aneuploid genomically unstable EEC displayed similar patterns of protein expression. This was in contrast to diploid stable EEC, which displayed a protein expression profile similar to normal endometrium. Approximately 10% of the differentially expressed proteins in EEC were specific for this type of cancer with differential expression of other proteins observed in other types of malignancy (e.g., SCC). Selected proteins differentially expressed in 2D gels of EEC were further analysed in an EEC precursor lesion, that is, atypical hyperplasia of endometrium, and showed increased expression of CLIC1, EIF4A1 and PRDX6 and decreased expression of ENO1, ANXA4, EMD and Ku70.Conclusion
Protein expression in diploid and aneuploid genomically unstable EEC is different from the expression profile of proteins in diploid genomically stable EEC. We showed that changes in expression of proteins typical for EEC could already be detected in precursor lesions, that is, atypical hyperplasia of endometrium, highlighting their clinical potential for improving early diagnostics of EEC.
SUBMITTER: Lomnytska MI
PROVIDER: S-EPMC3314786 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundThe aim of the study was to analyze the expression of nuclear receptor interacting protein 1 (NRIP1) and its partner ligand-dependent nuclear receptor co-repressor (LCOR) in endometrioid endometrial cancer and to investigate their association with estrogen receptor (ER), progesterone receptor (PR), Ki-67, clinicopathological parameters and patient survival.Materials and methodsImmunohistochemical evaluation was carried out to investigate the subcellular expression of NRIP1 and LCOR in endometrioid endometrial cancer samples. Statistical analysis was used to identify the correlations of NRIP1 and LCOR expression with clinicopathological variables and to estimate the survival rates.ResultsEndometrial cancer tissues exhibited higher expression of NRIP1 and LCOR in comparison with the normal tissues. Cytoplasmic LCOR expression was positively associated with ER and PR expression, while cytoplasmic NRIP1 expression was positively associated with ER expression. Moreover, cytoplasmic expression of NRIP1 was positively associated with Ki-67.ConclusionOur study demonstrated that high cytoplasmic expression of LCOR may predict a longer overall survival of patients with endometrioid endometrial cancer. Patients with tumors expressing low levels of LCOR showed a worse survival compared to those expressing high levels.
| S-EPMC8408693 | biostudies-literature
Project description:The identification of novel molecular markers and the development of cancer treatment strategies are very important as cancer incidence is still very high. Obesity can contribute to cancer progression, including endometrial cancer. Adipocytes secrete leptin, which, when at a high level, is associated with an increased risk of cancer. The aim of this study was to determine the expression profile of leptin-related genes in the endometrial tissue samples and whole blood of patients. The study material included tissue samples and whole blood collected from 30 patients with endometrial cancer and 30 without cancer. Microarrays were used to assess the expression profile of leptin-related genes. Then, the expression of leptin (LEP), leptin receptor (LEPR), leptin receptor overlapping transcript (LEPROT), and leptin receptor overlapping transcript-like 1 (LEPROTL1) was determined by the Real-Time Quantitative Reverse Transcription Reaction (RT-qPCR). The serum leptin concentration was evaluated using Enzyme-linked immunosorbent assay (ELISA). Leptin and its receptors were overexpressed both at the mRNA and protein levels. Furthermore, there were strong positive correlations between leptin levels and patient Body Mass Index (BMI). Elevated levels of leptin and its receptors may potentially contribute to the progression of endometrial cancer. These observations may be useful in designing endometrial cancer treatment strategies.
| S-EPMC8268664 | biostudies-literature
Project description:ObjectiveThis study aims to investigate the expression of γ-synuclein in endometrioid endometrial carcinoma and assess if the γ-synuclein expression correlates with the aggression of the tumour and its prognostic value in endometrioid endometrial carcinoma.DesignThis retrospective study evaluated (60) specimens of the primary untreated endometrioid endometrial carcinoma and (12) normal endometrium tissues, and the expression of γ-synuclein was checked by immunohistochemistry. The correlation between γ-synuclein expression and the clinicopathological features of patients with endometrioid endometrial carcinoma was analysed, and SPSS V.13.0 software was used for statistical analysis.ResultsThe expression of γ-synuclein was positive in 48.3% (29/60) endometrioid endometrial carcinomas compared with the control group, and the difference was significant (p=0.001). The expression level of γ-synuclein in endometrioid endometrial carcinoma was closely associated with FIGO (International Federation of Gynecology and Obstetrics) stages, the depth of myometrial invasion and lymph nodes metastases (p<0.05), but not correlated with the histopathological grades, the patient's age and the expression of ER (estrogen receptor) and PR (progesterone receptor) (p>0.05). In univariate and multivariate analyses, the γ-synuclein expression was significantly associated with a shorter overall survival (95% CI 1.429 to 101.892, p=0.020).ConclusionsThis study suggests that the expression of γ-synuclein is expected to be a useful marker for endometrioid endometrial carcinoma invasion, metastasis and prognosis in endometrioid endometrial carcinoma.
| S-EPMC3341596 | biostudies-literature
Project description:PURPOSE:Endometrioid endometrial carcinoma (EEC) is the major histologic type of endometrial cancer, the most prevalent gynecologic malignancy in the United States. EEC recurrence or metastasis is associated with a poor prognosis. Early-stage EEC is generally curable, but a subset has high risk of recurrence or metastasis. Prognosis estimation for early-stage EEC mainly relies on clinicopathologic characteristics, but is unreliable. We aimed to identify patients with high-risk early-stage EEC who are most likely to benefit from more extensive surgery and adjuvant therapy by building a prognostic model that integrates clinical variables and protein markers. EXPERIMENTAL DESIGN:We used two large, independent early-stage EEC datasets as training (n = 183) and validation cohorts (n = 333), and generated the levels of 186 proteins and phosphoproteins using reverse-phase protein arrays. By applying an initial filtering and the elastic net to the training samples, we developed a prognostic model for overall survival containing two clinical variables and 18 protein markers and optimized the risk group classification. RESULTS:The Kaplan-Meier survival analyses in the validation cohort confirmed an improved discriminating power of our prognostic model for patients with early-stage EEC over key clinical variables (log-rank test, P = 0.565 for disease stage, 0.567 for tumor grade, and 1.3 × 10(-4) for the integrative model). Compared with clinical variables (stage, grade, and patient age), only the risk groups defined by the integrative model were consistently significant in both univariate and multivariate analyses across both cohorts. CONCLUSIONS:Our prognostic model is potentially of high clinical value for stratifying patients with early-stage EEC and improving their treatment strategies.
| S-EPMC4715969 | biostudies-literature
Project description:The objective of this study was to determine whether lower expression levels of DICER1 are associated with disease recurrence in patients with endometrioid endometrial cancer. The authors also explored DNA methylation and haploinsufficiency as potential mechanisms related to altered DICER1 expression in these tumors.DICER1 expression was assessed by quantitative polymerase chain reaction in a selected cohort of endometrioid endometrial tumors (N = 169). Loss of heterozygosity analyses were conducted using 2 single nucleotide polymorphisms, and combined bisulfate restriction analysis was used to assess methylation in the 5'-untranslated region of DICER1 in representative tumors. The correlations between DICER1 expression and clinicopathologic variables, including overall survival (OS) and disease-free survival (DFS), were assessed using nonparametric rank-sum tests and Cox proportional hazard models as appropriate. Survival distributions were described using the Kaplan-Meier method. A nested case-control analysis was conducted to confirm the association between transcript levels and disease recurrence.Lower DICER1 expression (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.05-1.75; P = .02) and advanced disease stage (HR, 2.79; 95%CI, 1.59-4.90; P < .001) were associated with worse DFS. Three variables were associated significantly with reduced OS: age (HR, 1.04; 95%CI, 1.02-1.06; P < .0001), advanced disease stage (HR, 6.41; 95%CI, 3.57-11.52; P < .0001), and high tumor grade (HR, 2.96; 95%CI, 1.46-5.99; P = .003). Nested case-control analyses confirmed that there were lower DICER1 transcript levels in patients who had recurrent disease (P = .01). Deletion of DICER1 sequences was an infrequent event (5% of analyzed patients), and no methylation was observed in the 5' DICER1 regulatory region.Lower DICER1 transcript levels were correlated with disease recurrence and worse DFS survival in patients with endometrioid endometrial cancer. The factors that influence DICER1 transcript levels in primary endometrial cancers remain unknown.
| S-EPMC3065965 | biostudies-literature
Project description:ObjectiveTo identify the optimal adjuvant treatment regimen for patients with endometrioid and non-endometrioid node-positive endometrial cancer.MethodsWe retrospectively identified 249 women with FIGO 2009 stage IIIC endometrial cancer at our institution who underwent surgical staging from 1985 to 2015 followed by external beam radiotherapy (RT), chemotherapy (CT), or a combination of CT + RT. Survival rates were calculated using the Kaplan-Meier method.ResultsThe 5-year disease-specific survival (DSS) rate for all patients was 65%. Adjuvant CT + RT conferred higher rates of 5-year DSS as compared to CT alone in patients with grade 3 endometrioid and non-endometrioid tumors (61% vs. 27%, P = 0.04 and 67% vs. 38%, P = 0.02, respectively). Among patients with non-endometrioid tumors, treatment with concurrent chemoradiotherapy followed by additional sequential chemotherapy had higher 5-year DSS rates than with concurrent chemoradiotherapy alone (74% vs. 50%, P = 0.02). The 3-year pelvic recurrence rate was 5% with RT ± CT and 35% with CT alone (P < 0.001) for all patients. No paraaortic nodal failures were observed following extended-field RT, but 14% of patients who received pelvic-only RT or CT alone developed recurrences in the paraaortic nodes (P < 0.001).ConclusionsCombined-modality therapy including adjuvant external beam pelvic radiotherapy yields excellent outcomes for patients with all subtypes of node-positive endometrial cancer. The most pronounced DSS advantage from adjuvant chemoradiotherapy was evident in women with non-endometrioid endometrial cancer.
| S-EPMC7523189 | biostudies-literature
Project description:Endometrial cancer (EC) incidence and mortality continues to rise. Molecular profiling of EC promises improvement of risk assessment and treatment selection. Though, we still lack robust and accurate models to predict those at risk of failing treatment. The objective of this pilot study is to create models with clinical and genomic data that will discriminate patients with EC at risk of disease recurrence. We performed a pilot, retrospective, case-control study evaluating patients with EC, endometrioid type: 7 with recurrence of disease (cases), and 54 without (controls). RNA was extracted from frozen specimens and sequenced (RNAseq). Genomic features from RNAseq included transcriptome expression, genomic, and structural variation. Feature selection for variable reduction was performed with univariate ANOVA with cross-validation. Selected variables, informative for EC recurrence, were introduced in multivariate lasso regression models. Validation of models was performed in machine learning platforms (ML) and independent datasets (TCGA). The best performing prediction models (out of >170) contained the same lncRNA features (AUC of 0.9, and 95% CI: 0.75, 1.0). Models were validated with excellent performance in ML platforms and good performance in an independent dataset. Prediction models of EC recurrence containing lncRNA features have better performance than models with clinical data alone
2022-11-02 | GSE216872 | GEO
Project description:OBJECTIVE:This study aimed to develop a prediction model for lymph node metastasis using a gene expression signature in patients with endometrioid-type endometrial cancer. METHODS:Newly diagnosed endometrioid-type endometrial cancer cases in which the patients had undergone lymphadenectomy during a surgical staging procedure were identified from a national dataset (N = 330). Clinical and pathologic data were extracted from patient medical records, and gene expression datasets of their tumors were used to create a 12-gene predictive model for lymph node metastasis. We used principal components analysis on a training set (n = 110) to develop multivariate logistic models to predict low-risk patients having a probability of lymph node metastasis of less than 4%. The model with the highest prediction performance was selected for an evaluation set (n = 112), which, in turn, was validated in an independent validation set (n = 108). RESULTS:The model applied to the evaluation set showed 100% sensitivity (90% confidence interval [CI], 74%-100%) and 42% specificity (90% CI, 34%-51%), which resulted in 100% negative predictive value (90% CI, 89%-100%). In the validation set, we confirmed that the model consistently showed 100% sensitivity (90% CI, 88%-100%), 42% specificity (90% CI, 32%-50%), and 100% negative predictive value (90% CI, 88%-100%). CONCLUSIONS:Our 12-gene signature model is a useful tool for the identification of patients with endometrioid-type endometrial cancer at low risk of lymph node metastasis, particularly given that it can be used to analyze histologic tissue before surgery and used to tailor surgical options.
| S-EPMC5780243 | biostudies-other
Project description:PURPOSE:Endometrioid endometrial cancers (EEC) frequently harbor coexisting mutations in phosphoinositide 3-kinase (PI3K) pathway genes, including PTEN, PIK3CA, PIK3R1, and KRAS. We sought to define the genetic determinants of PI3K pathway inhibitor response in EEC cells, and whether PTEN-mutant EEC cell lines rely on p110? signaling for survival. EXPERIMENTAL DESIGN:Twenty-four human EEC cell lines were characterized for their mutation profile and activation state of PI3K and mitogen-activated protein kinase (MAPK) signaling pathway proteins. Cells were treated with pan-class I PI3K, p110?, and p110? isoform-specific, allosteric mTOR, mTOR kinase, dual PI3K/mTOR, mitogen-activated protein/extracellular signal-regulated kinase (MEK), and RAF inhibitors. RNA interference (RNAi) was used to assess effects of KRAS silencing in EEC cells. RESULTS:EEC cell lines harboring PIK3CA and PTEN mutations were selectively sensitive to the pan-class I PI3K inhibitor GDC-0941 and allosteric mTOR inhibitor temsirolimus, respectively. Subsets of EEC cells with concurrent PIK3CA and/or PTEN and KRAS mutations were sensitive to PI3K pathway inhibition, and only 2 of 6 KRAS-mutant cell lines showed response to MEK inhibition. KRAS RNAi silencing did not induce apoptosis in KRAS-mutant EEC cells. PTEN-mutant EEC cell lines were resistant to the p110? inhibitors GSK2636771 and AZD6482, and only in combination with the p110? selective inhibitor A66 was a decrease in cell viability observed. CONCLUSIONS:Targeted pan-PI3K and mTOR inhibition in EEC cells may be most effective in PIK3CA- and PTEN-mutant tumors, respectively, even in a subset of EECs concurrently harboring KRAS mutations. Inhibition of p110? alone may not be sufficient to sensitize PTEN-mutant EEC cells and combination with other targeted agents may be required.
| S-EPMC3700760 | biostudies-literature
Project description:PurposeChanges in the activity of endothelins and their receptors may promote neoplastic processes. They can be caused by epigenetic modifications and modulators, but little is known about endothelin-3 (EDN3), particularly in endometrial cancer. The aim of the study was to determine the expression profile of endothelin family and their interactions with miRNAs, and to assess the degree of EDN3 methylation.MethodsThe study enrolled 45 patients with endometrioid endometrial cancer and 30 patients without neoplastic changes. The expression profile of endothelins and their receptors was determined with mRNA microarrays and RT-qPCR. The miRNA prediction was based on the miRNA microarray experiment and the mirDB tool. The degree of EDN3 methylation was assessed by MSP.ResultsEDN1 and EDNRA were overexpressed regardless of endometrial cancer grade, which may be due to the lack of regulatory effect of miR-130a-3p and miR-485-3p, respectively. In addition, EDN3 and EDNRB were significantly downregulated.ConclusionThe endothelial axis is disturbed in endometrioid endometrial cancer. The observed silencing of EDN3 activity may be mainly due to DNA methylation.
| S-EPMC10356642 | biostudies-literature