scholarly journals Multiscale-omic assessment of EWSR1-NFATc2 fusion positive sarcomas identifies the mTOR pathway as a potential therapeutic target

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Nathan D. Seligson ◽  
Richard D. Maradiaga ◽  
Colin M. Stets ◽  
Howard M. Katzenstein ◽  
Sherri Z. Millis ◽  
...  
Keyword(s):  
Ewing Sarcoma ◽  
Additional Data ◽  
Gene Expression Omnibus ◽  
Mtor Pathway ◽  
The Cancer Genome Atlas ◽  
Molecular Characteristics ◽  
Potential Therapeutic Target ◽  
Disease Stabilization ◽  
Cancer Genome Atlas ◽  
Ewing Family Of Tumors

AbstractSarcomas harboring EWSR1-NFATc2 fusions have historically been categorized and treated as Ewing sarcoma. Emerging evidence suggests unique molecular characteristics and chemotherapy sensitivities in EWSR1-NFATc2 fusion positive sarcomas. Comprehensive genomic profiles of 1024 EWSR1 fusion positive sarcomas, including 14 EWSR1-NFATc2 fusions, were identified in the FoundationCore® database. Additional data from the Gene Expression Omnibus, the Genomics of Drug Sensitivity in Cancer and The Cancer Genome Atlas datasets were included for analysis. EWSR1-NFATc2 fusion positive sarcomas were genomically distinct from traditional Ewing sarcoma and demonstrated upregulation of the mTOR pathway. We also present a case of a 58-year-old male patient with metastatic EWSR1-NFATc2 fusion positive sarcoma who achieved 47 months of disease stabilization when treated with combination mTOR and VEGF inhibition. EWSR1-NFATc2 fusion positive sarcomas are molecularly distinct entities with overactive mTOR signaling; which may be therapeutically targetable. These findings support the use of precision medicine in the Ewing family of tumors.

scholarly journals Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) in Pancreatic Ductal Adenocarcinoma (PDA): An integrative analysis of a novel therapeutic target

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ritu Pandey ◽  
Muhan Zhou ◽  
Shariful Islam ◽  
Baowei Chen ◽  
Natalie K Barker ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Target ◽  
Cell Activity ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Wild Type ◽  
Cancer Genome Atlas ◽  
Novel Therapeutic

AbstractWe investigated biomarker CEACAM6, a highly abundant cell surface adhesion receptor that modulates the extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDA). The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) RNA-Seq data from PDA patients were analyzed for CEACAM6 expression and evaluated for overall survival, association, enrichment and correlations. A CRISPR/Cas9 Knockout (KO) of CEACAM6 in PDA cell line for quantitative proteomics, mitochondrial bioenergetics and tumor growth in mice were conducted. We found CEACAM6 is over-expressed in primary and metastatic basal and classical PDA subtypes. Highest levels are in classical activated stroma subtype. CEACAM6 over-expression is universally a poor prognostic marker in KRAS mutant and wild type PDA. High CEACAM6 expression is associated with low cytolytic T-cell activity in both basal and classical PDA subtypes and correlates with low levels of T-REG markers. In HPAF-II cells knockout of CEACAM6 alters ECM-cell adhesion, catabolism, immune environment, transmembrane transport and autophagy. CEACAM6 loss increases mitochondrial basal and maximal respiratory capacity. HPAF-II CEACAM6−/− cells are growth suppressed by >65% vs. wild type in mice bearing tumors. CEACAM6, a key regulator affects several hallmarks of PDA including the fibrotic reaction, immune regulation, energy metabolism and is a novel therapeutic target in PDA.

scholarly journals Data mining of immune-related prognostic genes in metastatic melanoma microenvironment

2020 ◽  
Vol 40 (11) ◽  
Author(s):  
Wei Han ◽  
Biao Huang ◽  
Xiao-Yu Zhao ◽  
Guo-Liang Shen
Keyword(s):  
Gene Expression ◽  
Tumor Microenvironment ◽  
Metastatic Melanoma ◽  
Interaction Network ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Protein Protein Interaction ◽  
Subtype Identification ◽  
Cancer Genome Atlas ◽  
Immune Related Genes

Abstract Skin cutaneous melanoma (SKCM) is one of the most deadly malignancies. Although immunotherapies showed the potential to improve the prognosis for metastatic melanoma patients, only a small group of patients can benefit from it. Therefore, it is urgent to investigate the tumor microenvironment in melanoma as well as to identify efficient biomarkers in the diagnosis and treatments of SKCM patients. A comprehensive analysis was performed based on metastatic melanoma samples from the Cancer Genome Atlas (TCGA) database and ESTIMATE algorithm, including gene expression, immune and stromal scores, prognostic immune-related genes, infiltrating immune cells analysis and immune subtype identification. Then, the differentially expressed genes (DEGs) were obtained based on the immune and stromal scores, and a list of prognostic immune-related genes was identified. Functional analysis and the protein–protein interaction network revealed that these genes enriched in multiple immune-related biological processes. Furthermore, prognostic genes were verified in the Gene Expression Omnibus (GEO) databases and used to predict immune infiltrating cells component. Our study revealed seven immune subtypes with different risk values and identified T cells as the most abundant cells in the immune microenvironment and closely associated with prognostic outcomes. In conclusion, the present study thoroughly analyzed the tumor microenvironment and identified prognostic immune-related biomarkers for metastatic melanoma.

scholarly journals Clinical Significance of miR-210 and its Prospective Signaling Pathways in Non-Small Cell Lung Cancer: Evidence from Gene Expression Omnibus and the Cancer Genome Atlas Data Mining with 2763 Samples and Validation via Real-Time Quantitative PCR

2018 ◽  
Vol 46 (3) ◽  
pp. 925-952 ◽  
Author(s):  
Rong-quan He ◽  
Wei-luan Cen ◽  
Jie-mei Cen ◽  
Wei-ning Cen ◽  
Jia-yi Li ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Meta Analysis ◽  
Gene Expression Omnibus ◽  
Small Cell ◽  
The Cancer Genome Atlas ◽  
Small Cell Lung ◽  
Free Survival ◽  
Real Time Quantitative Pcr ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Background/Aims: Since the function of microRNA (miR)-210 in non-small cell lung cancer (NSCLC) remains unclear, we aimed to explore the clinical significance of miR-210 in NSCLC. Methods: NSCLC-related data from 1673 samples on Gene Expression Omnibus and 1090 samples on The Cancer Genome Atlas were obtained and analyzed. The expression level of miR-210 was validated via real-time quantitative PCR analysis with 125 paired clinical samples. A meta-analysis was performed to generate a comprehensive understanding of miR-210 expression and its clinical significance in NSCLC. In addition, bioinformatics analysis was also conducted to reveal the potential underlying mechanism of miR-210 action in NSCLC. Results: miR-210 expression was consistently elevated in NSCLC solid tissue samples. However, its expression was controversial in easily obtained body fluids (i.e., blood, plasma, and serum). Moreover, an overall pooled meta-analysis implied a comparatively higher level of miR-210 expression in NSCLC cancerous tissue than in normal control tissue (P < 0.001). In addition, a meta-analysis of outcome revealed a significant diagnostic capacity of miR-210 in NSCLC by detecting its expression in serum and sputum (area under the summary receiver operating characteristic curve 0.82 and 0.81, respectively). miR-210 overexpression was associated with poor progression-free survival (PFS) in NSCLC and was negatively related to overall survival and disease-free survival. Bioinformatic gene enrichment and annotation analyses showed that the target genes of miR-210 were greatly enriched in cell adhesion and plasma membrane, and three pathways were considered to be the main functional circuits of miR-210: renin secretion, the cGMP-PKG signaling pathway, and cell adhesion molecules. Conclusion: In NSCLC, miR-210 expression was elevated and overexpression indicated poor PFS. Expression level of miR-210 in serum and sputum showed significant diagnostic value for NSCLC.

Identification of novel mRNA-miRNA-lncRNA competing endogenous RNA network associated with prognosis of breast cancer

Epigenomics ◽  
2019 ◽  
Vol 11 (13) ◽  
pp. 1501-1518 ◽  
Author(s):  
Guansheng Zhong ◽  
Weiyang Lou ◽  
Minya Yao ◽  
Chengyong Du ◽  
Haiyan Wei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Cancer Prognosis ◽  
Competing Endogenous Rna ◽  
Hub Genes ◽  
Cerna Network ◽  
Competing Endogenous Rna Network ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Aim: To identify novel competing endogenous RNA (ceRNA) network related to patients prognosis in breast cancer. Materials & methods: Dysregulated mRNA based on intersection of three Gene Expression Omnibus and The Cancer Genome Atlas datasets were analyzed by bioinformatics. Results: In total 72 upregulated and 208 downregulated genes were identified. Functional analysis showed that some pathways related to cancer were significantly enriched. By means of stepwise reverse prediction and validation from mRNA to lncRNA, 19 hub genes, nine key miRNA and four key lncRNAs were identified by expression and survival analysis. Ultimately, the coexpression analysis identified RRM2-let-7a-5p- SNHG16/ MAL2 as key ceRNA subnetwork associated with prognosis of breast cancer. Conclusion: We successfully constructed a novel ceRNA network, among which each component was significantly associated with breast cancer prognosis.

scholarly journals Deciphering N6-Methyladenosine-Related Genes Signature to Predict Survival in Lung Adenocarcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Jie Zhu ◽  
Min Wang ◽  
Daixing Hu
Keyword(s):  
Lung Adenocarcinoma ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Consensus Clustering ◽  
Lasso Regression ◽  
Gene Expressions ◽  
Tumor Tissues ◽  
Cancer Genome Atlas ◽  
Selection Operator ◽  
Cox Analysis

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death. Among these, lung adenocarcinoma (LUAD) accounts for most cases. Due to the improvement of precision medicine based on molecular characterization, the treatment of LUAD underwent significant changes. With these changes, the prognosis of LUAD becomes diverse. N6-methyladenosine (m6A) is the most predominant modification in mRNAs, which has been a research hotspot in the field of oncology. Nevertheless, little has been studied to reveal the correlations between the m6A-related genes and prognosis in LUAD. Thus, we conducted a comprehensive analysis of m6A-related gene expressions in LUAD patients based on The Cancer Genome Atlas (TCGA) database by revealing their relationship with prognosis. Different expressions of the m6A-related genes in tumor tissues and non-tumor tissues were confirmed. Furthermore, their relationship with prognosis was studied via Consensus Clustering Analysis, Principal Components Analysis (PCA), and Least Absolute Shrinkage and Selection Operator (LASSO) Regression. Based on the above analyses, a m6A-based signature to predict the overall survival (OS) in LUAD was successfully established. Among the 479 cases, we found that most of the m6A-related genes were differentially expressed between tumor and non-tumor tissues. Six genes, HNRNPC, METTL3, YTHDC2, KIAA1429, ALKBH5, and YTHDF1 were screened to build a risk scoring signature, which is strongly related to the clinical features pathological stages (p<0.05), M stages (p<0.05), T stages (p < 0.05), gender (p=0.04), and survival outcome (p=0.02). Multivariate Cox analysis indicated that risk value could be used as an independent prognostic factor, revealing that the m6A-related genes signature has great predictive value. Its efficacy was also validated by data from the Gene Expression Omnibus (GEO) database.

scholarly journals High expression levels of pyrimidine metabolic rate–limiting enzymes are adverse prognostic factors in lung adenocarcinoma: a study based on The Cancer Genome Atlas and Gene Expression Omnibus datasets

2020 ◽  
Vol 16 (3) ◽  
pp. 347-366 ◽  
Author(s):  
Haiwei Wang ◽  
Xinrui Wang ◽  
Liangpu Xu ◽  
Ji Zhang ◽  
Hua Cao
Keyword(s):  
Lung Cancer ◽  
Metabolic Rate ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
High Expression ◽  
Pyrimidine Metabolism ◽  
Expression Levels ◽  
Cancer Genome Atlas ◽  
Rate Limiting ◽  
Genome Atlas

Abstract Reprogramming of metabolism is described in many types of cancer and is associated with the clinical outcomes. However, the prognostic significance of pyrimidine metabolism signaling pathway in lung adenocarcinoma (LUAD) is unclear. Using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets, we found that the pyrimidine metabolism signaling pathway was significantly enriched in LUAD. Compared with normal lung tissues, the pyrimidine metabolic rate–limiting enzymes were highly expressed in lung tumor tissues. The high expression levels of pyrimidine metabolic–rate limiting enzymes were associated with unfavorable prognosis. However, purinergic receptors P2RX1, P2RX7, P2RY12, P2RY13, and P2RY14 were relatively downregulated in lung cancer tissues and were associated with favorable prognosis. Moreover, we found that hypo-DNA methylation, DNA amplification, and TP53 mutation were contributing to the high expression levels of pyrimidine metabolic rate–limiting enzymes in lung cancer cells. Furthermore, combined pyrimidine metabolic rate–limiting enzymes had significant prognostic effects in LUAD. Comprehensively, the pyrimidine metabolic rate–limiting enzymes were highly expressed in bladder cancer, breast cancer, colon cancer, liver cancer, and stomach cancer. And the high expression levels of pyrimidine metabolic rate–limiting enzymes were associated with unfavorable prognosis in liver cancer. Overall, our results suggested the mRNA levels of pyrimidine metabolic rate–limiting enzymes CAD, DTYMK, RRM1, RRM2, TK1, TYMS, UCK2, NR5C2, and TK2 were predictive of lung cancer as well as other cancers.

scholarly journals Downstream Neighbor of SON (DONSON) Expression Is Enhanced in Phenotypically Aggressive Prostate Cancers

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3439 ◽  
Author(s):  
Niklas Klümper ◽  
Marthe von Danwitz ◽  
Johannes Stein ◽  
Doris Schmidt ◽  
Anja Schmidt ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Locally Advanced ◽  
Metastatic Potential ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Cancer Genome Atlas ◽  
Prostate Cancers ◽  
Migration Capacity

Downstream neighbor of Son (DONSON) plays a crucial role in cell cycle progression and in maintaining genomic stability, but its role in prostate cancer (PCa) development and progression is still underinvestigated. Methods: DONSON mRNA expression was analyzed with regard to clinical-pathological parameters and progression using The Cancer Genome Atlas (TCGA) and two publicly available Gene Expression Omnibus (GEO) datasets of PCa. Afterwards, DONSON protein expression was assessed via immunohistochemistry on a comprehensive tissue microarray (TMA). Subsequently, the influence of a DONSON-knockdown induced by the transfection of antisense-oligonucleotides on proliferative capacity and metastatic potential was investigated. DONSON was associated with an aggressive phenotype in the PCa TCGA cohort, two GEO PCa cohorts, and our PCa TMA cohort as DONSON expression was particularly strong in locally advanced, metastasized, and dedifferentiated carcinomas. Thus, DONSON expression was notably upregulated in distant and androgen-deprivation resistant metastases. In vitro, specific DONSON-knockdown significantly reduced the migration capacity in the PCa cell lines PC-3 and LNCaP, which further suggests a tumor-promoting role of DONSON in PCa. In conclusion, the results of our comprehensive expression analyses, as well as the functional data obtained after DONSON-depletion, lead us to the conclusion that DONSON is a promising prognostic biomarker with oncogenic properties in PCa.

scholarly journals Downregulated SPINK4 is associated with poor survival in colorectal cancer

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Xiaojie Wang ◽  
Qian Yu ◽  
Waleed M. Ghareeb ◽  
Yiyi Zhang ◽  
Xingrong Lu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Expression Data ◽  
Poor Survival ◽  
Protein Levels ◽  
Normal Tissues ◽  
Human Protein Atlas ◽  
Cancer Genome Atlas ◽  
Independent Indicator

Abstract Background SPINK4 is known as a gastrointestinal peptide in the gastrointestinal tract and is abundantly expressed in human goblet cells. The clinical significance of SPINK4 in colorectal cancer (CRC) is largely unknown. Methods We retrieved the expression data of 1168 CRC patients from 3 Gene Expression Omnibus (GEO) datasets (GSE24551, GSE39582, GSE32323) and The Cancer Genome Atlas (TCGA) to compare the expression level of SPINK4 between CRC tissues and normal colorectal tissues and to evaluate its value in predicting the survival of CRC patients. At the protein level, these results were further confirmed by data mining in the Human Protein Atlas and by immunohistochemical staining of samples from 81 CRC cases in our own center. Results SPINK4 expression was downregulated in CRC compared with that in normal tissues, and decreased SPINK4 expression at both the mRNA and protein levels was associated with poor prognosis in CRC patients from all 3 GEO datasets, the TCGA database and our cohort. Additionally, lower SPINK4 expression was significantly related to higher TNM stage. Moreover, in multivariate regression, SPINK4 was confirmed as an independent indicator of poor survival in CRC patients in all databases and in our own cohort. Conclusions We concluded that reduced expression of SPINK4 relates to poor survival in CRC, functioning as a novel indicator.

Identification of T-cell-inflamed gastric adenocarcinoma in The Cancer Genome Atlas (TCGA).

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 16-16 ◽  
Author(s):  
Steven Brad Maron ◽  
Jason John Luke ◽  
Raymond Hovey ◽  
Riyue Bao ◽  
Thomas Gajewski ◽  
...  
Keyword(s):  
T Cell ◽  
Objective Response ◽  
Copy Number Variations ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Molecular Characteristics ◽  
Chi Square ◽  
Primary Tumors ◽  
Cancer Genome Atlas ◽  
Genome Atlas

16 Background: Gastroesophageal adenocarcinoma (GEC) is a significant global health problem. KEYNOTE-012 demonstrated a 22% objective response rate in patients with PD-L1 expressing GEC that received pembrolizumab. A subset of patients (pts) tumors express a T cell “inflamed” (TCI) phenotype, which can be measured using an IFN-γ-based immune signature and may prove more predictive of clinical benefit. Using a 160 gene RNA-Seq immune expression profile, we sought to characterize the molecular environments of TCI versus non-TCI GEC patients in The Cancer Genome Atlas (TCGA). Methods: 395 GEC pts with primary tumors in TCGA were clustered into TCI, non-TCI, and intermediate subtypes using both unsupervised hierarchical and K-means clustering (k = 3). Molecular characteristics were categorized using data acquired via CbioPortal and the UCSC Xena repository. Only non-silent somatic mutations and copy number variations (CNVs) reaching GISTIC2 -2 or +2 thresholds were considered. Statistical comparisons were performed using chi-square, ANOVA, and t-test. Results: The TCI subtype contained patients from all TCGA-defined subtypes - EBV-associated (56%), MSI-high (16%), chromosomal unstable (6%), and genomically stable (27%). No significant differences were seen between TCI and non-TCI for tumor site or stage. Mutations in PTEN, PIK3CA, CDH1, and RHOA were more frequent in TCI patients. ERBB2, CCNE1, and KRAS CNVs were infrequent in TCI patients as were PDE4D deletions ( p< 0.05 ). TCI tumors had higher expression of both co-inhibitory (PD-1, PD-L1/L2, CD28/80, BTLA, LAG3) and co-stimulatory (CD137/40/27, OX40, GITR, ICOS) checkpoint molecules ( p< 10-7). Total mutation burden was no different between TCI and non-TCI pts when excluding MSI-high pts nor when assessing MSI-high alone. Conclusions: The IFN immune phenotype encompassed GEC patients from all TCGA subsets. Correlation of clinical outcome with checkpoint blockade is necessary to confirm these molecular associations and the independent predictive utility of this immune-profile stratification.

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