Nestin expression identifies ependymoma patients with poor outcome.
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ABSTRACT:
SUBMITTER: Milde T
PROVIDER: S-EPMC8057643 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeSteroid hormones and growth factors affect lung cancer, and it is possible they act in concert to influence patient outcome.Experimental designPrimary lung tumors and normal lung tissue were analyzed for expression and localization of estrogen receptor α and β-1 (ERα and ERβ), aromatase, progesterone receptor (PR), and epidermal growth factor receptor (EGFR).ResultsTumors expressed higher levels of ERβ compared to matched normal lung, whereas the reverse was true of PR. High cytoplasmic ERβ expression was identified as an independent negative prognostic predictor of overall survival (OS; HR = 1.67), and low total PR was identified as an independent negative predictor of time to progression (TTP; HR = 1.59). After adjusting for stage, age, sex, and smoking, combined high cytoplasmic ERβ and low total PR showed enhanced effects on OS (HR = 2.64) and on TTP (HR = 6.02). Further effects on OS were observed when EGFR expression was included (HR = 5.32). Patients with low cytoplasmic ERβ, low aromatase, low EGFR, and high total PR had shorter OS than patients with the opposite pattern (HR = 6.60). Contribution of these markers to survival showed no significant sex differences in a multivariable model. ERα was elevated in tumors but was not predictive of survival, and appears to represent a variant ERα protein that is only recognized by a C-terminal antibody.ConclusionsHormonal and EGFR pathways together may contribute to lung cancer prognosis. Lung tumors with high ERβ-1/low PR may define patients with aggressive biology. A validation study is necessary to fully assess the predictive value of these markers.
| S-EPMC3064257 | biostudies-literature
Project description:Metabolic reprogramming is a hallmark of cancer. Epithelial-mesenchymal transition (EMT) induces cancer stem cell (CSC) characteristics and promotes tumor invasiveness; however relatively little is known about the metabolic reprogramming in EMT. Here we show that breast epithelial cells undergo metabolic reprogramming following EMT. Relative to control, cell lines expressing EMT transcription factors show ?1.5-fold accumulation of glutamine, glutamate, beta-alanine and glycylleucine as well as ?1.5-fold reduction of phosphoenolpyruvate, urate, and deoxycarnitine. Moreover, these metabolic alterations were found to be predictive of overall survival (hazard ratio = 2.3 (95% confidence interval: 1.31-4.2), logrank p-value = 0.03) and define breast cancer molecular subtypes. EMT-associated metabolites are primarily composed of anapleurotic precursors, suggesting that cells undergoing EMT have a shift in energy production. In summary, we describe a unique panel of metabolites associated with EMT and demonstrate that these metabolites have the potential for predicting clinical and biological characteristics associated with patient survival.
| S-EPMC4767460 | biostudies-literature
Project description:In this era of molecular diagnostics, prediction of clear-cell renal cell cancer (ccRCC) survival requires optimization, as current prognostic markers fail to determine individual patient outcome. Epigenetic events are promising molecular markers. Promoter CpG island methylation of cysteine dioxygenase type 1 (CDO1), which was identified as prognostic marker for breast cancer, is studied as a potential marker for ccRCC survival.We collected primary tissues of 365 ccRCC cases identified within the prospective Netherlands Cohort Study (NLCS). In this population-based series, CDO1 promoter methylation was observed in 124 of 324 (38.3%) patients with successful methylation-specific PCR analysis. Kaplan-Meier curves and Wilcoxon tests were used to evaluate 10-year ccRCC-specific survival. Cox regression analysis was used to obtain crude and multivariate HRs and 95% confidence intervals (CI). The relative prognostic value of multivariate models with and without CDO1 promoter methylation was compared using likelihood-ratio tests.Patients with CDO1 promoter methylation have a significantly poorer survival than those without (Wilcoxon P = 0.006). Differences in survival were independent of other prognostic factors, including age and sex (HR, 1.66; 95% CI, 1.12-2.45) and TNM stage, tumor size, and Fuhrman grade (HR, 1.89; 95% CI, 1.25-2.85). Multivariate models performed better with than without CDO1 promoter methylation status (likelihood-ratio P = 0.003). Survival curves were validated in an independent series of 280 ccRCC cases from The Cancer Genome Atlas (TCGA; Wilcoxon P < 0.001).CDO1 promoter methylation may not substitute common prognostic makers to predict ccRCC survival, but offers additional, relevant prognostic information, indicating that it might be a novel molecular marker to determine ccRCC prognosis.
| S-EPMC4612631 | biostudies-literature
Project description:Recent studies show that mantle cell lymphoma (MCL) express aberrant miRNA profiles, however, the clinical effect of miRNA expression has not previously been examined and validated in prospective, large, homogenously treated cohorts. We analyzed diagnostic MCL samples from the Nordic MCL2 and MCL3 clinical trials, in which all patients had received Rituximab-high-dose cytarabin alternating with Rituximab-maxiCHOP, followed by BEAM and autologous stem cell support. We performed genome-wide miRNA microarray profiling of 74 diagnostic MCL samples from the MCL2 trial (screening cohort). Differentially expressed miRNAs were re-analyzed by qRT-PCR. Prognostic miRNAs were validated by qRT-PCR in diagnostic MCL samples from 94 patients of the independent MCL3 trial (validation cohort). Three miRNAs (miR-18b, miR-92a, miR-378d) were significantly differentially expressed in patients who died from MCL in both the screening- and the validation cohort. MiR-18b was superior to miR-92a and miR-378d in predicting high risk. Thus, we generated a new MIPI-B-miR prognosticator, combining expression-levels of miR-18b with MIPI-B data. This prognosticator improved identification of high risk patients compared to MIPI-B with regard to cause-specific survival (P=0.015), overall survival (P=0.006) and progression-free survival (P<0.001). Transfection of two MCL cell lines with miR-18b decreased their proliferation rate without inducing apoptosis, suggesting miR-18b may render MCL cells resistant to chemotherapy by decelerating cell proliferation. Thus, we conclude that overexpression of miR-18b identifies patients with poor prognosis in two large prospective MCL cohorts and adds prognostic information to MIPI-B. MiR-18b may reduce the proliferation rate of MCL cells as a mechanism of chemoresistance.
2015-04-01 | GSE66299 | GEO
Project description:The 52-kDa FK506-binding protein (FKBP52), a regulator of steroid hormone receptor signaling, is potentially involved in a variety of hormone-dependent cancer types. The present study investigated the expression and clinical implications of FKBP52 in breast cancer. Immunohistochemistry was performed on samples from 145 breast cancer patients and on 66 unmatched breast non-cancerous tissues (as controls) to determine the expression level of FKBP52. Publicly available microarray and RNA-seq datasets used in the present study were downloaded from the European Bioinformatics Institute ArrayExpress. Kaplan-Meier survival analysis was also performed. FKBP52 expression was moderately higher in the tumors than that in the non-cancerous tissues, but this difference was not statistically significant (P=0.176). However, available microarray datasets exhibited a significant difference in FKBP52 mRNA levels between breast tumors and controls. In the 145 breast cancer patients, elevated FKBP52 expression was significantly associated with advanced Tumor-Node-Metastasis (TNM) stage (P=0.015), lymph node metastasis (P=0.015) and tumors with poor histological differentiation (P=0.047). FKBP52 expression was negatively associated with estrogen receptor expression (P=0.033), but positively associated with human epidermal growth factor receptor 2 expression (P=0.033). However, there was no association between FKBP52 and progesterone receptor expression. Survival analyses demonstrated that FKBP52 was indicative of a poor overall survival rate (P=0.026), which was consistent with the result of Kaplan-Meier analysis, exhibiting a negative association between the mRNA of FKBP52 and overall survival (OS) (P=0.044). Other than for FKBP52 [hazard ratio (HR), 2.315; 95% confidence interval (CI), 1.077-4.975; P=0.032], univariate analysis revealed that clinical stage exhibited a significant influence on the prognosis of the breast cancer patients (HR, 2.148; 95% CI, 1.011-4.566; P=0.047). However, multivariate analysis revealed that only clinical stage, not FKBP52, was an independent prognostic factor (HR, 2.721; 95% CI, 1.169-6.335; P=0.020). Patients were further classified according to their OS. Compared with the controls (3.94±2.992), FKBP52 expression in breast cancer patients with OS of ≤3 years (5.39±3.409; P=0.042) or OS of ≤5 years (5.88±3.473; P=0.005) was significantly increased, respectively. However, no significant difference in FKBP52 expression was observed between controls and individuals with an OS time of >3 years (4.84±3.769; P=0.109) or >5 years (5.32±3.372; P=0.090). Elevated FKBP52 expression may be involved in tumor progression and invasion, given its positive association with TNM stage and lymph node metastasis. Although it is not an independent predictor, FKBP52 has promise as a biological marker for estimating the progression of breast cancer.
| S-EPMC5652253 | biostudies-literature
Project description:Objectives: Small cell lung cancer (SCLC) is an aggressive and highly metastatic lung cancer subtype. Nestin is a member of the intermediate filament family and serves as a potential proliferative and multipotency marker in neural progenitor and stem cells. Aberrant expression of nestin is linked to poor prognosis in different cancers, including non-small cell lung cancer. However, the association between nestin expression and clinicopathological feature or prognosis has remained unclear for SCLC. This study examined whether nestin expression was associated with malignant features and clinical outcomes in SCLC. Materials and Methods: Using previously established Nestin knock-down cells and a newly established Nestin-overexpressing cell line, we examined the relationship between nestin expression and cell proliferation in vitro and in vivo and chemosensitivity. We also analyzed nestin expression in three drug-resistant lung cancer cell lines. Furthermore, we examined samples from 84 SCLC patients (16 patients with surgical resection, and 68 patients with biopsy), and immunohistochemically analyzed nestin expression. Results: Nestin expression correlated positively with cell proliferation, but negatively with chemosensitivity. Nestin expression in drug-resistant cell lines was upregulated compared to their parental cells. Among the 84 SCLC patients, 24 patients (28.6%) showed nestin-positive tumor. Nestin-positive ratio tended to be higher in operated patients than in biopsied patients. Nestin-positive and -negative patients showed no significant differences in response rate (RR) or progression-free survival (PFS) following first-line chemotherapy. However, positive expression of nestin was associated with shorter PFS following second-line chemotherapy (median PFS: nestin-positive, 81 days vs. nestin-negative, 117 days; P = 0.029). Conclusions: Nestin expression may be associated with malignant phenotype and worse outcome in SCLC patients.
| S-EPMC7438916 | biostudies-literature
Project description:In order to improve our understanding of breast cancer (BC) biology and its prognostication, global miRNA expression profiling was performed using microarray technology on systemically untreated BC patients with long-term follow up. In this study, global miRNA expression profiling using microarray technology was conducted on 56 systemically untreated BC patients with long-term follow up. The arrays used for miRNAs expression profiling comprise a total of 640 probes targeting 328 human miRNAs (hsa-miRs), as well as mouse and rat miRNAs, from the miRBase Sequence Database version 8.0.
| S-ECPF-GEOD-28321 | biostudies-other
Project description:Adult T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy still associated with poor outcome calling for new therapeutic options. DNA methylation landscapes of adult T-ALL remain largely uncharacterized. Here, we systematically analyzed the DNA methylation profiles of normal thymic sorted T-cell subpopulations and 143 primary adult T-ALLs as part of French GRAALL 2003-2005 trial. Our results indicated that T-ALL is epigenetically distinct from normal T-cell subpopulations and consisted of five major subtypes (C1-C5) which were either associating with co-occurring DNMT3A/IDH2 mutations (C1), TAL1 deregulation (C2), TLX3 (C3), TLX1/in cis-HOXA9 (C4) or in trans-HOXA9 (C5) overexpression. Importantly, our data identified an unexpected subset of hypermethylated T-ALL associated with poor outcome and primary therapeutic response. Using mouse xenografts, we showed that hypermethylated T-ALL samples displayed therapeutic response to the DNA hypomethylating agent, 5-Azacitidine, which significantly delayed tumor progression suggesting epigenetic-based therapies as a novel treatment option in hypermethylated T-ALL.
2021-03-01 | GSE147667 | GEO
Project description:PurposeAberrant microRNA (miRNA) expression is associated with cancer and has potential diagnostic and prognostic value in various malignancies. In this study, we investigated miRNA profiling as a complementary tool to improve our understanding of breast cancer (BC) biology and to assess whether miRNA expression could predict clinical outcome of BC patients.Experimental designGlobal miRNA expression profiling using microarray technology was conducted in 56 systemically untreated BC patients who had corresponding mRNA expression profiles available. Results were further confirmed using qRT-PCR in an independent dataset of 89 ER-positive BC patients homogeneously treated with tamoxifen only. MiR-210 functional analyses were performed in MCF7 and MDA-MB-231 BC cell lines using lentiviral transduction.ResultsEstrogen receptor (ER) status, tumor grade and our previously developed gene expression grade index (GGI) were associated with distinct miRNA profiles. Several miRNAs were found to be clinically relevant, including miR-210, its expression being associated with tumor proliferation and differentiation. Furthermore, miR-210 was associated with poor clinical outcome in ER-positive, tamoxifen-treated BC patients. Interestingly, the prognostic performance of miR-210 was similar to several reported multi-gene signatures, highlighting its important role in BC differentiation and tumor progression. Functional analyses in BC cell lines revealed that miR-210 is involved in cell proliferation, migration and invasion.ConclusionsThis integrated analysis combining miRNA and mRNA expression demonstrates that miRNA expression provides additional biological information beyond mRNA expression. Expression of miR-210 is linked to tumor proliferation and appears to be a strong potential biomarker of clinical outcome in BC.
| S-EPMC3126805 | biostudies-literature
Project description:Ependymal tumors are the third most common group of brain tumors in children, accounting for about 10% of all primary brain neoplasms. According to the current WHO classification, they comprise four entities with the most frequent ependymoma and anaplastic ependymoma. The most of pediatric tumors are located within the posterior fossa, with a tendency to infiltrate the vital brain structures. This limits surgical resection and poses a considerable clinical problem. Moreover, there are no appropriate outcome prognostic factors besides the extent of surgical resection. Despite definition of molecular subgroups, the majority of childhood ependymomas present a balanced genome, which makes it difficult to establish molecular prognostic factors.The purpose of our study was to explore whether miRNA expression could be used as prognostic markers in pediatric infratentorial ependymomas. We also performed a mRNA expression pattern analysis of NELL2 and LAMA2 genes, with immunohistochemical illustrations of representative cases. The miRNA and mRNA expression was measured in 53 pediatric infratentorial ependymomas using a real-time quantitative PCR.Three miRNAs were shown to efficiently differentiate between grade II and III ependymomas: miR-17-5p, miR-19a-3p, and miR-106b-5p. Survival analysis showed that the probabilities of overall (p = 0.036) and event-free survival (p = 0.002) were reduced with higher than median miRNA expression levels of miR-17-5p. Using multivariate analysis adjusted for patient's age, sex, tumor grade and localization, we showed statistically significant associations with event-free survival (p = 0004) and borderline statistical significance with overall survival (p = 0.057) for miR-17-5p. Correlation analysis of miR-19a, miR-17-5p, miR-106b revealed that their expression levels were significantly correlated with EZH2 expression, suggested marker of PFA ependymomas. Furthermore, lower expression level of LAMA2 mRNA was shown to be associated with an increased risk of death in covariate-adjusted analyses.Our data provide a better understanding of pediatric ependymoma and suggests the presence of plausible molecular biomarkers connected with the outcome.
| S-EPMC4938415 | biostudies-literature