The Microenvironment Combining with Immune Infiltration of Uveal Melanoma

2021 ◽  
Author(s):  
Daowei Zhang ◽  
Jiawen Wu ◽  
Jihong Wu ◽  
Shenghai Zhang
Keyword(s):  
Uveal Melanoma ◽  
Immune Cells ◽  
Therapeutic Targets ◽  
Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Malignant Tumours ◽  
Cancer Genome Atlas ◽  
Key Genes ◽  
Low Expression

Abstract Background: Uveal melanoma (UM) is the most common intraocular malignancy in adults. Although immunotherapy provided novel options in the disease's progression, it only benefits a minority of patients. The understanding of the UM microenvironment and the potential therapeutic targets in the microenvironment is still undefined. We aimed to propose a novel classification of UM microenvironment to identify ideal biomarkers for prognosis and potential targets for effective immunotherapy.Methods: In this study, we obtained the gene expression profile of 80 UM patients from the Cancer Genome Atlas (TCGA) and calculated immune/stromal scores based on the Estimation of stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm dividing patients into the high- and low-expression groups. Then, 1024 immune-related differently expressed genes (DEGs) were selected in total following the annotation and enrichment analysis and key genes were screened by PPI network. Consequently, we conducted CIBERSORT algorithm and TIMER database to analyses the correlation between key genes and immune cells as well as utilized GeneCards database to analyses the correlation between key genes and the disease. Additionally, GSVA was performed to enrich the nonparametric and unsupervised signaling pathways of key genes and the drug sensitivity of them were predicted.Results: Based on high- and low-expression groups, we found that there were 888 up-regulated DEGs and 126 down-regulated DEGs in total, which were mainly enriched in 4 pathways in GO and 3 pathways in KEGG. Combining with the 10 genes screened by PPI, KM-plot showed that B2M and HLA-B were significantly affected the survival of UM patients. Among 22 immune cells, B2M and HLA-B were mainly corelated with 11 of them. GSVA results revealed 42 pathways significantly enriched of B2M while 41 pathways enriched of HLA-B. Finally, we predicted the Paclitaxel as the hopefully treatment for HLA-B.Conclusions: Our study not only understands deeper of fundamental biological features of microenvironment but also with potential therapeutic targets of UM.

scholarly journals Opposite Roles of BAP1 in Overall Survival of Uveal Melanoma and Cutaneous Melanoma

2020 ◽  
Vol 9 (2) ◽  
pp. 411 ◽  
Author(s):  
Feng Liu-Smith ◽  
Yunxia Lu
Keyword(s):  
Overall Survival ◽  
Uveal Melanoma ◽  
Cutaneous Melanoma ◽  
Cox Regression ◽  
Enrichment Analysis ◽  
Copy Number Variations ◽  
The Cancer Genome Atlas ◽  
Small Subset ◽  
Mrna Levels ◽  
Cancer Genome Atlas

Background: BRCA1-Associated Protein 1 (BAP1) germline mutations predispose individuals to cancers, including uveal melanoma (UM) and cutaneous melanoma (CM). BAP1 loss is common in UM and is associated with a worse prognosis. BAP1 loss is rare in CM and the outcome is unclear. Methods: UM and CM data was retrieved from The Cancer Genome Atlas (TCGA) database. Cox regression model was performed to examine whether BAP1 mRNA levels or copy number variations were associated with overall survival (OS). Results: BAP1-low mRNA predicted a poor OS in UM (HR = 9.57, 95% CI: 2.82, 32.5) but a contrasting better OS in CM (HR = 0.73, 95% CI: 0.56, 0.95). These results remained unchanged after adjusting for sex, age, and stage in UM and CM, or after adjusting for ulceration or Breslow depth in CM. Additionally, low BAP1 mRNA predicted a better OS in CM patients older than 50 years but not in younger patients. Co-expression and enrichment analysis revealed differential genes and mutations that were correlated with BAP1 expression levels in UM and CM tumors. Conclusions: Low BAP1 mRNA was significantly associated with a better OS in CM patients, in sharp contrast to UM. High BAP1 expression in CM was significantly associated with over-expressed CDK1, BCL2, and KIT at the protein level which may explain the poor OS in this sub-group of patients. Function of BAP1 was largely different in CM and UM despite of a small subset of shared co-expressed genes.

Genetic Analysis of Uveal Melanoma in 658 Patients Using the Cancer Genome Atlas Classification of Uveal Melanoma as A, B, C, and D

Ophthalmology ◽  
2019 ◽  
Vol 126 (10) ◽  
pp. 1445-1453 ◽  
Author(s):  
Pornpattana Vichitvejpaisal ◽  
Lauren A. Dalvin ◽  
Mehdi Mazloumi ◽  
Kathryn G. Ewens ◽  
Arupa Ganguly ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Uveal Melanoma ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Cancer Genome Atlas ◽  
Genome Atlas

scholarly journals Multi-Platform Omics Analysis for Identification of Molecular Characteristics and Therapeutic Targets of Uveal Melanoma

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yong Joon Kim ◽  
Seo Jin Park ◽  
Kyung Joo Maeng ◽  
Sung Chul Lee ◽  
Christopher Seungkyu Lee
Keyword(s):  
Uveal Melanoma ◽  
Copy Number ◽  
Checkpoint Inhibitors ◽  
Therapeutic Targets ◽  
The Cancer Genome Atlas ◽  
Molecular Characteristics ◽  
Synthetic Lethal ◽  
Whole Exome ◽  
Cancer Genome Atlas ◽  
Sirna Library

AbstractCurrently, there is no effective treatment for metastatic uveal melanoma (UVM). Here, we aimed to identify the mechanism involving intrinsic chemoresistance of metastatic UVM and the relevant therapeutic targets for UVM. We analyzed cohorts of 80 and 67 patients with primary UVM and skin cutaneous melanoma (SKCM), respectively, using The Cancer Genome Atlas dataset. Mutational burdens identified by whole exome sequencing were significantly lower in UVM than in SKCM patients. COSMIC mutational signature analysis identified that most of the mutations in UVM patients (>90%) were associated with spontaneous deamination of 5-methylcytosine or defective mismatch repair. Transcriptome analysis revealed that the MYC signature was more enriched in UVM patients, as compared to SKCM patients. Fifty-nine (73.8%) of 80 UVM patients showed gains in MYC copy number, and a high MYC copy number was associated with aggressive clinicopathological features of tumors and poor survival. Kinome-wide siRNA library screening identified several therapeutic targets, reported as synthetic lethal targets for MYC-addicted cancers. Notably, UVM cell lines showed high susceptibility to a WEE1 inhibitor (MK-1775; adavosertib) at a clinically tolerable dose. Overall, our study identified high MYC activity in UVM, and suggested G2/M checkpoint inhibitors as effective therapeutic targets for UVM.

scholarly journals A four-gene signature predicts survival and anti-CTLA4 immunotherapeutic responses based on immune classification of melanoma

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Ying Mei ◽  
Mei-Ju May Chen ◽  
Han Liang ◽  
Li Ma
Keyword(s):  
Enrichment Analysis ◽  
Gene Signature ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Gene Set Enrichment ◽  
Malignant Skin ◽  
Cancer Genome Atlas ◽  
Melanoma Patients ◽  
Potential Use

AbstractCutaneous melanoma is the most malignant skin cancer. Biomarkers for stratifying patients at initial diagnosis and informing clinical decisions are highly sought after. Here we classified melanoma patients into three immune subtypes by single-sample gene-set enrichment analysis. We further identified a four-gene tumor immune-relevant (TIR) signature that was significantly associated with the overall survival of melanoma patients in The Cancer Genome Atlas cohort and in an independent validation cohort. Moreover, when applied to melanoma patients treated with the CTLA4 antibody, ipilimumab, the TIR signature could predict the response to ipilimumab and the survival. Notably, the predictive power of the TIR signature was higher than that of other biomarkers. The genes in this signature, SEL1L3, HAPLN3, BST2, and IFITM1, may be functionally involved in melanoma progression and immune response. These findings suggest that this four-gene signature has potential use in prognosis, risk assessment, and prediction of anti-CTLA4 response in melanoma patients.

scholarly journals CSIG-03. RECONCILING TUMOR HETEROGENEITY IN GLIOBLASTOMA USING A PATHWAY-BASED APPROACH

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii28-ii28
Author(s):  
Alvaro Alvarado ◽  
Kaleab Tessema ◽  
Kunal Patel ◽  
Riki Kawaguchi ◽  
Richard Everson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Patient Survival ◽  
Molecular Subtype ◽  
Gene List ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Molecular Architecture ◽  
Survival Pathways ◽  
Cancer Genome Atlas

Abstract Despite efforts to gain a deeper understanding of its molecular architecture, glioblastoma (GBM) remains uniformly fatal. While genome-based molecular subtyping has revealed that GBMs may be parsed into several molecularly distinct categories, this insight has yielded little progress towards extending patient survival. In particular, the great phenotypic heterogeneity of GBM – both inter and intratumorally – has hindered therapeutic efforts. To this end, we interrogated tumor samples using a pathway-based approach to resolve tumoral heterogeneity. Gene set enrichment analysis (GSEA) was applied to gene expression data and used to provide an overview of each sample that can be compared to other samples by generating sample clusters based on overall patterns of enrichment. The Cancer Genome Atlas (TCGA) samples were clustered using the canonical and oncogenic signatures and in both cases the clustering was distinct from the molecular subtype previously reported and clusters were informative of patient survival. We also analyzed single cell RNA sequencing datasets and uniformly found two clusters of cells enriched for cell cycle regulation and survival pathways. We have validated our approach by generating gene lists from common elements found in the top contributing genesets for a particular cluster and testing the top targets in appropriate gliomasphere patient-derived lines. Samples enriched for cell cycle related genesets showed a decrease in sphere formation capacity when E2F1, out top target, was silenced and when treated with fulvestrant and calcitriol, which were identified as potential drugs targeting this genelist. Conversely, no changes were observed in samples not enriched for this gene list. Finally, we interrogated spatial heterogeneity and found higher enrichment of the proliferative signature in contrast enhancing compared with non-enhancing regions. Our studies relate inter- and intratumoral heterogeneity to critical cellular pathways dysregulated in GBM, with the ultimate goal of establishing a pipeline for patient- and tumor-specific precision medicine.

scholarly journals Identification of key genes associated with lung adenocarcinoma by bioinformatics analysis

2021 ◽  
Vol 104 (1) ◽  
pp. 003685042199727
Author(s):  
Xinyu Wang ◽  
Jiaojiao Yang ◽  
Xueren Gao
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Cox Regression ◽  
Enrichment Analysis ◽  
Tumor Stage ◽  
Gene Expression Omnibus ◽  
Poor Overall Survival ◽  
Key Genes ◽  
Low Expression

Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer, comprising around 40% of all lung cancer. Until now, the pathogenesis of LUAD has not been fully elucidated. In the current study, we comprehensively analyzed the dysregulated genes in lung adenocarcinoma by mining public datasets. Two sets of gene expression datasets were obtained from the Gene Expression Omnibus (GEO) database. The dysregulated genes were identified by using the GEO2R online tool, and analyzed by R packages, Cytoscape software, STRING, and GPEIA online tools. A total of 275 common dysregulated genes were identified in two independent datasets, including 54 common up-regulated and 221 common down-regulated genes in LUAD. Gene Ontology (GO) enrichment analysis showed that these dysregulated genes were significantly enriched in 258 biological processes (BPs), 27 cellular components (CCs), and 21 molecular functions (MFs). Furthermore, protein-protein interaction (PPI) network analysis showed that PECAM1, ENG, KLF4, CDH5, and VWF were key genes. Survival analysis indicated that the low expression of ENG was associated with poor overall survival (OS) of LUAD patients. The low expression of PECAM1 was associated with poor OS and recurrence-free survival of LUAD patients. The cox regression model developed based on age, tumor stage, ENG, PECAM1 could effectively predict 5-year survival of LUAD patients. This study revealed some key genes, BPs, CCs, and MFs involved in LUAD, which would provide new insights into understanding the pathogenesis of LUAD. In addition, ENG and PECAM1 might serve as promising prognostic markers in LUAD.

scholarly journals High RPS27A Expression Predicts Poor Prognosis in Patients With HPV Type 16 Cervical Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Qiming Wang ◽  
Yan Cai ◽  
Xuewen Fu ◽  
Liang Chen
Keyword(s):  
Cervical Cancer ◽  
Poor Prognosis ◽  
Biological Significance ◽  
Enrichment Analysis ◽  
Hpv Infection ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Protein Protein Interaction ◽  
Cervical Cancer Cells ◽  
Cancer Genome Atlas

In recent years, the incidence and the mortality rate of cervical cancer have been gradually increasing, becoming one of the major causes of cancer-related death in women. In particular, patients with advanced and recurrent cervical cancers present a very poor prognosis. In addition, the vast majority of cervical cancer cases are caused by human papillomavirus (HPV) infection, of which HPV16 infection is the main cause and squamous cell carcinoma is the main presenting type. In this study, we performed screening of differentially expressed genes (DEGs) based on The Cancer Genome Atlas (TCGA) database and GSE6791, constructed a protein–protein interaction (PPI) network to screen 34 hub genes, filtered to the remaining 10 genes using the CytoHubba plug-in, and used survival analysis to determine that RPS27A was most associated with the prognosis of cervical cancer patients and has prognostic and predictive value for cervical cancer. The most significant biological functions and pathways of RPS27A enrichment were subsequently investigated with gene set enrichment analysis (GSEA), and integration of TCGA and GTEx database analyses revealed that RPS27A was significantly expressed in most cancer types. In this study, our analysis revealed that RPS27A can be used as a prognostic biomarker for HPV16 cervical cancer and has biological significance for the growth of cervical cancer cells.

scholarly journals The Prognostic Significance of MAFK and its Methylation in Cervical Cancer

2021 ◽  
Author(s):  
Mengjun Zhang ◽  
Hao Li ◽  
Yuan Liu ◽  
Siyu Hou ◽  
Ping Cui ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Prognostic Significance ◽  
Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cancer Prognosis ◽  
Aberrant Methylation ◽  
Cancer Data ◽  
Drug Candidates ◽  
Cancer Genome Atlas ◽  
Cancer Tissues

Abstract Background: The purpose of this study was to determine the value of MAFK as a biomarker of cervical cancer prognosis and to explore its methylation and possible cellular signaling pathways. Methods: We analyzed the cervical cancer data of The Cancer Genome Atlas (TCGA) through bioinformatics, including MAFK expression, methylation, prognosis and genome enrichment analysis. Results: MAFK expression was higher in cervical cancer tissues and was negatively correlated with the methylation levels of five CpG sites. MAFK is an independent prognostic factor of cervical cancer and is involved in the Nod-like receptor signaling pathway. CMap analysis screened four drug candidates for cervical cancer treatment. Conclusions: We confirmed that MAFK is a novel prognostic biomarker for cervical cancer and aberrant methylation may also affect MAFK expression and carcinogenesis. This study provides a new molecular target for the prognostic evaluation and treatment of cervical cancer.

scholarly journals ALG3 Contributes to the Malignant Biological Properties of Oral Squamous Cell Carcinoma Cells Through Regulating CDK-Cyclin Pathway

2020 ◽  
Author(s):  
Peihong Shao ◽  
Chengshi Wei ◽  
Yun Wang
Keyword(s):  
Western Blot ◽  
Colony Formation ◽  
Enrichment Analysis ◽  
Biological Properties ◽  
The Cancer Genome Atlas ◽  
Cell Counting ◽  
Invasion And Migration ◽  
Elevated Expression ◽  
Cancer Genome Atlas ◽  
And Migration

Abstract Background: In this study, we planned to investigate the function and potential mechanisms of Alpha-1,3-mannosyltransferase (ALG3) in oral squamous cell carcinoma (OSCC). Methods: Data from The Cancer Genome Atlas (TCGA) was used to analyze ALG3 expression and its effect on the prognosis of patients with OSCC. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was applied to explore the signaling pathways related to ALG3. In OSCC cells, ALG3 expression was measured by qPCR and western blot. Cell counting kit-8, colony formation, and transwell assays were implemented to detect the effects of ALG3 on the malignant biological properties OSCC cells. The expression of key proteins related to CDK-Cyclin pathway was detected by western blot. Results: The expression of ALG3 in OSCC samples was higher than that of the control samples, and the increase of ALG3 expression was related to unfavorable prognosis of OSCC patients. Additionally, the elevated expression of ALG3 was associated with pathological stage, lymph node metastasis and primary lesion in OSCC patients. ALG3 depletion blocked the growth, colony formation, invasion and migration of OSCC cells, while over-expression ALG3 reversed these phenomena. Moreover, exhaustion of ALG3 resulted in decreased expression of MCM7, CCNB2, CDK1 and PCNA, while these phenomena were inversed after ALG3 up-regulation. Conclusions: The enhancement of ALG3 expression promoted the aggressive biological behaviors of OSCC cells probably by promoting CDK-Cyclin pathway.

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