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Elevated Expression of Gamma-Glutamyl Hydrolase Is Associated With Poor Prognosis and Altered Immune Signature in Uterine Corpus Endometrial Carcinoma.

ABSTRACT: Uterine corpus endometrial carcinoma (UCEC) is a common malignant tumor of the female reproductive system with poor prognosis in advanced, recurrent, and metastatic cases. Identification of reliable molecular markers will help in the development of clinical strategies for early detection, diagnosis, and intervention. Gamma-glutamyl hydrolase (GGH) is a key enzyme in folate metabolism pathway. High expression of GGH is associated with severe clinicopathological features and poor prognosis of several cancers. High GGH expression is also related to cell resistance to antifolate drugs such as methotrexate. In this study we focused on the prognostic value of immunohistochemical GGH expression level in UCEC tissue and RNA-seq data from The Cancer Genome Atlas to establish associations with clinical features and outcomes. Further, we conducted comprehensive bioinformatics analyses to identify and functionally annotate differentially expressed genes (DEGs) associated with UCEC upregulation and assessed the effects of upregulation on immune infiltration. Both GGH mRNA and protein expression levels were elevated in tumor tissues, and higher expression was significantly associated with advanced clinicopathological features and poor prognosis by univariate analysis. Further multivariate analysis identified elevated GGH expression as an independent risk factor for poor outcome. Nomograms including GGH expression yielded a c-index for disease-specific survival prediction of 0.884 (95% confidence interval: 0.861-0.907). A total of 520 DEGs (111 upregulated and 409 downregulated) were identified between high and low GGH expression groups. Analysis using Gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway, Gene set enrichment analysis, and protein‒protein interaction indicated significant associations of altered GGH expression with cell proliferation, immune response, and the occurrence and development of UCEC tumors. Finally, GGH expression level was associated with high Th2 cell and low natural killer CD56bright cell infiltration. Collectively, these findings indicate that GGH drives UCEC progression and could be a useful biomarker for survival prediction as well as a therapeutic target.

SUBMITTER: Yu C

PROVIDER: S-EPMC8785095 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Uterine corpus endometrial carcinoma (UCEC) is the most common type of gynecologic malignancy worldwide. Despite advances in the treatments of UCEC, its incidence and mortality rates are still increasing. N6-methyladenosine (m6A) is the most common form of RNA modification and has attracted increasing interest in cancer pathogenesis and progression. Thus, we aimed to identify the landscape of m6A regulators and build a prognostic gene signature in UCEC. In this study, we first analyzed copy number variations (CNVs), single nucleotide variations (SNVs) and gene expression profiles as well as matched clinical information of UCEC patients from The Cancer Genome Atlas (TCGA) database. Next, we determined that CNVs in m6A regulatory genes had a significant negative impact on patient survival. The mRNA expression levels of a total of 16 m6A regulators were significantly correlated with different CNV patterns. Using univariate Cox regression analysis, IGF2BP1, KIAA1429, IGF2BP3, YTHDF3, and IGF2BP2 were found to be closely associated with UCEC patient survival outcomes. Based on the least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression models, we built a 3-gene (IGF2BP3, KIAA1429 and IGF2BP1) signature of m6A regulators with prognostic value in UCEC that could effectively predict patient prognosis (log-rank test p-value < 0.0001). In addition, risk scores were significantly different between patients stratified by tumor stage, SNV, and CNV. Multivariate Cox regression analysis suggested that risk score might be an independent prognostic indicator for the overall survival of patients with UCEC (p-value < 0.05). Gene enrichment analysis indicated that high IGF2BP1 gene expression is associated with cytoplasmic stress granules. KIAA1429 gene expression is associated with cellular nucleic acid metabolism. The expression of the IGF2BP3 gene is associated with RNA binding processes. In conclusion, we determined that genetic alterations in m6A regulatory genes could be effective and reliable biomarkers for UCEC prognosis prediction.

Project description:Background: As the fourth most common malignant tumors in women, uterine corpus endometrial carcinoma (UCEC) requires novel and reliable biomarkers for prognosis prediction to improve the overall survival. Oxidative phosphorylation (OXPHOS) is found to be strongly correlated with the progression of tumor. Here, we aimed to construct an OXPHOS-related and immune microenvironment prognostic signature to stratify UCEC patients for optimization of treatment strategies. Method: Prognosis-associated OXPHOS-related differentially expressed genes were identified by multivariable Cox regression from TCGA-UCEC cohort. Based on the candidate genes, an OXPHOS-related prognostic signature was constructed by the train set data and verified by the entire set. When integrated with relevant clinical characteristics, a nomogram was also created for clinical application. Through comparison of tumor microenvironment between different risk groups, the underlying mechanism of the model and the inner correlation between immune microenvironment and energy metabolism were further investigated. Results: An OXPHOS-related signature containing ATP5IF1, COX6B1, FOXP3, and NDUFB11 was constructed and had better predictive ability compared with other recently published signatures in UCEC. Patients with lower risk score showed higher immune cell infiltration, higher ESTIMATE score (p = 2.808E-18), lower tumor purity (p = 2.808E-18), higher immunophenoscores (IPSs) (p < 0.05), lower expression of mismatch repair (MMR) proteins (p < 0.05), higher microsatellite instability (MSI), lower expression of markers of N6-methyladenosine (m6A) mRNA methylation regulators, higher tumor mutation burden (TMB) (p = 1.278E-9), and more sensitivity to immune checkpoint blockade (ICB) (p < 0.001) and chemotherapy drugs, thus, possessing improved prognosis. Conclusion: An OXPHOS-related and immune microenvironment prognostic signature classifying EC patients into different risk subsets was constructed in our study, which could be used to predict the prognosis of patients and help to select a specific subset of patients who might benefit from immunotherapy and chemotherapy, thus, improving the overall survival rate of UCEC. These findings may contribute to the discovery of novel and robust biomarkers or target therapy in UCEC and give new insights into the molecular mechanism of tumorigenesis and progression of UCEC.

Project description:Background:Uterine corpus endometrial carcinoma (UCEC) is a clinically heterogeneous disease, and this heterogeneity is associated with tumor development, clinical characteristics, and prognostic outcomes. Mutant-allele tumor heterogeneity (MATH) is a novel, non-biased, quantitative measure to assess intra-tumor heterogeneity based on next-generation sequencing data. We aimed to explore the use of MATH as a measure for tumor heterogeneity and its prognostic role in UCEC patients. Methods:We calculated MATH scores from the available data of 560 UCEC patients from The Cancer Genome Atlas (TCGA) and investigated their correlations with clinical characteristics, genetic alterations, and overall survival. Predictive accuracy was quantified using the area under the receiver operating characteristic curve (AUC) and the index of concordance (C-index). Results:In total, 242 MATH scores were obtained from the UCEC cohort. MATH scores were significantly related to age, race, cancer type, clinical stage, histological grade, molecular type, targeted molecular therapy, and hormonal therapy. Furthermore, the genomic pattern on the basis of MATH scores showed that mutation rates of TP53 (tumor protein p53) and ARID1A (AT-rich interaction domain 1A) were independently associated with MATH scores. Correlation analysis revealed a significantly positive association of MATH scores with the fraction of somatic copy number alteration (SCNA). Importantly, a high MATH score was significantly associated with shorter overall survival [hazard ratio (HR), 2.342; 95% confidence interval (CI), 1.110-4.942]. Multivariate Cox regression combined with stratified analysis revealed that the MATH score is an independent prognostic factor in UCEC patients under 60 years old, and predictive quantification showed the MATH score had an AUC of 0.756 and a C-index of 0.845. Conclusions:Our results suggest that MATH, a practical and useful way to measure intra-tumor heterogeneity, may serve as a significant biomarker for the prognosis of patients with UCEC, enabling more accurate prediction of clinical outcomes.

Project description:Mammaglobin B, also referred to as secretoglobin family 2A member 1 (SCGB2A1), has been reported to be highly expressed in uterine corpus endometrial cancer (UCEC) compared with in the normal endometrium. However, the prognostic value of SCGB2A1 in UCEC remains unclear. The Oncomine, The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium databases were used to explore the differential expression of SCGB2A1. Furthermore, data of patients with UCEC were downloaded from TCGA, and logistic regression analysis, survival analysis, univariate and multivariate analyses, and nomogram construction were performed to identify its prognostic value in UCEC. Additionally, gene set enrichment analysis (GSEA) was utilized to estimate the mechanisms of SCGB2A1 in UCEC. Finally, immune infiltration of SCGB2A1 in UCEC was analyzed using the Tumor Immune Estimation Resource. Decreased mRNA and protein expression levels of SCGB2A1 were significantly associated with poor prognostic clinicopathological characteristics (all P<0.05). Additionally, low expression levels of SCGB2A1 were associated with decreased survival of patients with UCEC compared with high expression levels of SCGB2A1. Furthermore, the independent prognostic value of SCGB2A1 in UCEC was identified by univariate and multivariate analyses. A nomogram based on 6 variables, including SCGB2A1 expression, was developed for the estimation of the 1-, 3-, and 5-year survival probability in UCEC. Additionally, GSEA suggested that the vascular endothelial growth factor, PTEN, platelet-derived growth factor, DNA repair, KRAS signaling, and PI3K-AKT-mTOR signaling pathways were differentially enriched in the low SCGB2A1 expression phenotype. Finally, high infiltration levels of CD8+ T cells were associated with SCGB2A1 in UCEC and this was associated with prognosis. The present results indicated that SCGB2A1 may be a promising independent prognostic factor in UCEC. These signaling pathways may be crucial for the regulation of UCEC via SCGB2A1.

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Elevated Expression of Gamma-Glutamyl Hydrolase Is Associated With Poor Prognosis and Altered Immune Signature in Uterine Corpus Endometrial Carcinoma.

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