Identification of TNFAIP8 as an Immune-Related Biomarker Associated With Tumorigenesis and Prognosis in Cutaneous Melanoma Patients

Tumor necrosis factor-α–induced protein 8 (TNFAIP8) is a member of the TIPE/TNFAIP8 family which is associated with inflammation and tumorigenesis. The potential role of TNFAIP8 in a tumor immune microenvironment in skin cutaneous melanoma (SKCM) has not yet been investigated. The TNFAIP8 expression was evaluated via gene expression profiling interactive analysis (GEPIA). We also evaluated the influence of TNFAIP8 on overall survival via GEPIA and PrognoScan. After GO and KEGG pathway analyses, the correlation between the TNFAIP8 expression level and immune cells or gene markers of the immune infiltration level was explored by R-language. The result showed the TNFAIP8 expression was significantly reduced in SKCM in comparison with normal control. In SKCM, the TNFAIP8 expression in higher levels was associated with the better overall survival. The high expression of TNFAIP8 was positively correlated with the immune score and promoted immune cell infiltration in SKCM patients. TNFAIP8 can be a positive prognosis marker or new immunotherapy target in SKCM.

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Database Mining of Genes of Prognostic Value for the Prostate Adenocarcinoma Microenvironment Using the Cancer Gene Atlas

BioMed Research International ◽

10.1155/2020/5019793 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Xin Zhao ◽

Daixing Hu ◽

Jia Li ◽

Guozhi Zhao ◽

Wei Tang ◽

...

Keyword(s):

Overall Survival ◽

Immune Cell ◽

Kegg Pathway ◽

Clinical Sample ◽

Expression Profiles ◽

Prostate Adenocarcinoma ◽

Cancer Gene ◽

Hub Genes ◽

Ppi Networks ◽

Pathway Analyses

Background. Prostate adenocarcinoma (PRAD) is a common malignant tumor in elderly men. Our research uses The Cancer Gene Atlas (TCGA) database to find potential related genes for predicting the prognosis of patients with PRAD. Methods. We downloaded gene expression profiles and clinical sample information from TCGA for 490 patients with PRAD (patient age: 41-78 years). We calculated stromal and immune scores using the ESTIMATE algorithm to predict the level of stromal and immune cell infiltration. We categorized patients with PRAD in TCGA into high and low score arrays according to their median immune/stromal scores and identified differentially expressed genes (DEGs) that were significantly correlated with the prognosis of PRAD. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. The association between DEGs and overall survival was investigated by weighted Kaplan–Meier survival analysis and multivariate analysis. Furthermore, the protein-protein interaction network (PPI) of DEGs was constructed using the STRING tool. Finally, the hub genes were identified by analyzing the degree of association of PPI networks. Results. We found that 8 individual DEGs, C6, S100A12, MLC1, PAX5, C7, FAM162B, CAMK1G, and TCEAL5, were significantly predictive of favorable overall survival and one DEG, EPYC, was associated with poor overall survival. GO and KEGG pathway analyses revealed that the DEGs were associated with immune responses. Moreover, 30 hub genes were obtained using the PPI network of DEGs: ITGAM, CD4, CD3E, IL-10, LCP2, ITGB2, ZAP-70, C3, CCL19, CXCL13, CXCL9, BTK, CCL21, CD247, CD28, CD3D, FCER1G, PTPRC, TYROBP, CCR5, ITK, CCL13, CCR1, CCR2, CD79B, CYBB, IL2RG, JAK3, PLCG2, and CD19. These prominent nodes had the most associations with other genes, indicating that they might play crucial roles in the prognosis of PRAD. Conclusions. We extracted a list of genes associated with the prostate adenocarcinoma microenvironment, which might contribute to the prediction and interpretation of PRAD prognosis.

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Comprehensive analysis identifies IFI16 as a novel signature associated with overall survival and immune infiltration of skin cutaneous melanoma

Cancer Cell International ◽

10.1186/s12935-021-02409-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Hanwen Wang ◽

Xiaoxia Xie ◽

Junyou Zhu ◽

Shaohai Qi ◽

Julin Xie

Keyword(s):

Overall Survival ◽

Cutaneous Melanoma ◽

Immune Cell ◽

Normal Skin ◽

Critical Role ◽

Comprehensive Analysis ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Discriminatory Ability ◽

Immune Infiltration

Abstract Background Skin cutaneous melanoma (SKCM) is the most common skin tumor with high mortality. The unfavorable outcome of SKCM urges the discovery of prognostic biomarkers for accurate therapy. The present study aimed to explore novel prognosis-related signatures of SKCM and determine the significance of immune cell infiltration in this pathology. Methods Four gene expression profiles (GSE130244, GSE3189, GSE7553 and GSE46517) of SKCM and normal skin samples were retrieved from the GEO database. Differentially expressed genes (DEGs) were then screened, and the feature genes were identified by the LASSO regression and Boruta algorithm. Survival analysis was performed to filter the potential prognostic signature, and GEPIA was used for preliminary validation. The area under the receiver operating characteristic curve (AUC) was obtained to evaluate discriminatory ability. The Gene Set Variation Analysis (GSVA) was performed, and the composition of the immune cell infiltration in SKCM was estimated using CIBERSORT. At last, paraffin-embedded specimens of primary SKCM and normal skin tissues were collected, and the signature was validated by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Results Totally 823 DEGs and 16 feature genes were screened. IFI16 was identified as the signature associated with overall survival of SKCM with a great discriminatory ability (AUC > 0.9 for all datasets). GSVA noticed that IFI16 might be involved in apoptosis and ultraviolet response in SKCM, and immune cell infiltration of IFI16 was evaluated. At last, FISH and IHC both validated the differential expression of IFI16 in SKCM. Conclusions In conclusion, our comprehensive analysis identified IFI16 as a signature associated with overall survival and immune infiltration of SKCM, which may play a critical role in the occurrence and development of SKCM.

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Screening of gene markers related to the prognosis of metastatic skin cutaneous melanoma based on Logit regression and survival analysis

BMC Medical Genomics ◽

10.1186/s12920-021-00923-0 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Guoliang Jia ◽

Zheyu Song ◽

Zhonghang Xu ◽

Youmao Tao ◽

Yuanyu Wu ◽

...

Keyword(s):

Gene Expression ◽

Cutaneous Melanoma ◽

Expression Profiles ◽

The Cancer Genome Atlas ◽

Training Dataset ◽

Validation Dataset ◽

Survival Prognosis ◽

Gene Markers ◽

Clinical Prognosis ◽

Logit Regression

Abstract Background Bioinformatics was used to analyze the skin cutaneous melanoma (SKCM) gene expression profile to provide a theoretical basis for further studying the mechanism underlying metastatic SKCM and the clinical prognosis. Methods We downloaded the gene expression profiles of 358 metastatic and 102 primary (nonmetastatic) CM samples from The Cancer Genome Atlas (TCGA) database as a training dataset and the GSE65904 dataset from the National Center for Biotechnology Information database as a validation dataset. Differentially expressed genes (DEGs) were screened using the limma package of R3.4.1, and prognosis-related feature DEGs were screened using Logit regression (LR) and survival analyses. We also used the STRING online database, Cytoscape software, and Database for Annotation, Visualization and Integrated Discovery software for protein–protein interaction network, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses based on the screened DEGs. Results Of the 876 DEGs selected, 11 (ZNF750, NLRP6, TGM3, KRTDAP, CAMSAP3, KRT6C, CALML5, SPRR2E, CD3G, RTP5, and FAM83C) were screened using LR analysis. The survival prognosis of nonmetastatic group was better compared to the metastatic group between the TCGA training and validation datasets. The 11 DEGs were involved in 9 KEGG signaling pathways, and of these 11 DEGs, CALML5 was a feature DEG involved in the melanogenesis pathway, 12 targets of which were collected. Conclusion The feature DEGs screened, such as CALML5, are related to the prognosis of metastatic CM according to LR. Our results provide new ideas for exploring the molecular mechanism underlying CM metastasis and finding new diagnostic prognostic markers.

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A novel pyroptosis-associated gene signature for immune status and prognosis of cutaneous melanoma

PeerJ ◽

10.7717/peerj.12304 ◽

2021 ◽

Vol 9 ◽

pp. e12304

Author(s):

Zhengyuan Wu ◽

Leilei Chen ◽

Chaojie Jin ◽

Jing Xu ◽

Xingqun Zhang ◽

...

Keyword(s):

Cutaneous Melanoma ◽

Immune Status ◽

Immune Cell ◽

Gene Signature ◽

Gene Set Enrichment Analysis ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Tumor Cell Death ◽

Prognostic Gene ◽

Prognostic Gene Signature

Background Cutaneous melanoma (CM) is a life-threatening destructive malignancy. Pyroptosis significantly correlates with programmed tumor cell death and its microenvironment through active host-tumor crosstalk. However, the prognostic value of pyroptosis-associated gene signatures in CM remains unclear. Methods Gene profiles and clinical data of patients with CM were downloaded from The Cancer Genome Atlas (TCGA) to identify differentially expressed genes associated with pyroptosis and overall survival (OS). We constructed a prognostic gene signature using LASSO analysis, then applied immune cell infiltration scores and Kaplan-Meier, Cox, and pathway enrichment analyses to determine the roles of the gene signature in CM. A validation cohort was collected from the Gene Expression Omnibus (GEO) database. Results Four pyroptosis-associated genes were identified and incorporated into a prognostic gene signature. Integrated bioinformatics findings showed that the signature correlated with patient survival and was associated with tumor growth and metastasis. The results of Gene Set Enrichment Analysis of a risk signature indicated that several enriched pathways are associated with cancer and immunity. The risk signature for immune status significantly correlated with tumor stem cells, the immune microenvironment, immune cell infiltration and immune subtypes. The expression of four pyroptosis genes significantly correlated with the OS of patients with CM and was related to the sensitivity of cancer cells to several antitumor drugs. A signature comprising four genes associated with pyroptosis offers a novel approach to the prognosis and survival of patients with CM and will facilitate the development of individualized therapy.

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CDCA3 Is a Novel Prognostic Biomarker Associated with Immune Infiltration in Hepatocellular Carcinoma

BioMed Research International ◽

10.1155/2021/6622437 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Zhihuai Wang ◽

Shuai Chen ◽

Gaochao Wang ◽

Sun Li ◽

Xihu Qin

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

Immune Cell ◽

Disease Free Survival ◽

In Silico Analysis ◽

Gene Markers ◽

Free Survival ◽

Immune Infiltration ◽

Normal Tissues ◽

Tumor Tissues

Cell division cycle-associated protein-3 (CDCA3) contributes to the regulation of the cell cycle. CDCA3 plays an important role in the carcinogenesis of various cancers; however, the association between CDCA3 expression, prognosis of patients, and immune infiltration in the tumor microenvironment is still unknown. Here, we demonstrated that CDCA3 was differentially expressed between the tumor tissues and corresponding normal tissues using in silico analysis in the ONCOMINE and Tumor Immune Estimation Resource (TIMER) databases. We analyzed the relationship between the expression of CDCA3 and prognosis of patients with hepatocellular carcinoma (HCC) using the Kaplan–Meier plotter database and Gene Expression Profiling Interactive Analysis (GEPIA). Furthermore, we determined the prognostic value of CDCA3 expression using univariate and multivariate analyses. We observed that CDCA3 expression closely correlated with immune infiltration and gene markers of infiltrating immune cells in the TIMER database. CDCA3 was highly expressed in the tumor tissues than in the adjacent normal tissues in various cancers, including HCC. Increased expression of CDCA3 was accompanied by poorer overall survival (OS), relapse-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). The correlation between CDCA3 expression and OS and disease-free survival (DFS) was also studied using GEPIA. CDCA3 expression was associated with the levels of immune cell infiltration and was positively correlated with tumor purity. Moreover, CDCA3 expression was associated with gene markers such as PD-1, CTLA4, LAG3, and TIM-3 from exhausted T cells, CD3D, CD3E, and CD2 from T cells, and TGFB1 and CCR8 located on the surface of Tregs. Thus, we demonstrated that CDCA3 may be a potential target and biomarker for the management and diagnosis of HCC.

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CXC Chemokines as Therapeutic Targets and Prognostic Biomarkers in Skin Cutaneous Melanoma Microenvironment

Frontiers in Oncology ◽

10.3389/fonc.2021.619003 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xuezhi Zhou ◽

Manjuan Peng ◽

Ye He ◽

Jingjie Peng ◽

Xuan Zhang ◽

...

Keyword(s):

Immune Cells ◽

Cutaneous Melanoma ◽

Immune Cell ◽

Gene Activation ◽

Skin Tumor ◽

Pathological Stage ◽

Normal Tissues ◽

The World ◽

Cxc Chemokine ◽

The Relationship

BackgroundSkin Cutaneous Melanoma (SKCM) is a tumor of the epidermal melanocytes induced by gene activation or mutation. It is the result of the interaction between genetic, constitutional, and environmental factors. SKCM is highly aggressive and is the most threatening skin tumor. The incidence of the disease is increasing year by year, and it is the main cause of death in skin tumors around the world. CXC chemokines in the tumor microenvironment can regulate the transport of immune cells and the activity of tumor cells, thus playing an anti-tumor immunological role and affecting the prognosis of patients. However, the expression level of CXC chemokine in SKCM and its effect on prognosis are still unclear.MethodOncomine, UALCAN, GEPIA, STRING, GeneMANIA, cBioPortal, TIMER, TRRUST, DAVID 6.8, and Metascape were applied in our research.ResultThe transcription of CXCL1, CXCL5, CXCL8, CXCL9, CXCL10, and CXCL13 in SKCM tissues were significantly higher than those in normal tissues. The pathological stage of SKCM patients is closely related to the expression of CXCL4, CXCL9, CXCL10, CXCL11, CXCL12, and CXCL13. The prognosis of SKCM patients with low transcription levels of CXCL4, CXCL9, CXCL10, CXCL11, and CXCL13 is better. The differential expression of CXC chemokines is mainly associated with inflammatory response, immune response, and cytokine mediated signaling pathways. Our data indicate that the key transcription factors of CXC chemokines are RELA, NF-κB1 and SP1. The targets of CXC chemokines are mainly LCK, LYN, SYK, MAPK2, MAPK12, and ART. The relationship between CXC chemokine expression and immune cell infiltration in SKCM was closed.ConclusionsOur research provides a basis for screening SKCM biomarkers, predicting prognosis, and choosing immunotherapy.

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Opposite roles of BAP1 in overall survival of uveal melanoma and cutaneous melanoma

10.21203/rs.2.15589/v1 ◽

2019 ◽

Author(s):

Feng Liu-Smith

Keyword(s):

Overall Survival ◽

Uveal Melanoma ◽

Cutaneous Melanoma ◽

Cox Regression ◽

Survival Function ◽

Poor Overall Survival ◽

Cox Regression Analysis ◽

Oncogenic Pathways ◽

Cellular Context ◽

Age Of Diagnosis

Abstract Background: BAP1 germline mutations predispose individuals to a number of cancer types including uveal melanoma (UM) and cutaneous melanoma (CM) which are distinctively different in the oncogenic pathways. BAP1 loss was common in UM and was associated with a worse prognosis. BAP1 loss was rare in CM and the outcome was unclear. Methods: This study used TCGA UM and CM databases for survival analysis for patients with different BAP1 status and mRNA expression levels. Cox regression model was used for adjusting to known prognosis factors. Results: BAP1- (loss or low expression) predicted a poor overall survival in UM (Cox HR = 0.062, logrank p =0.007) but a contrasting better overall survival in CM (HR = 1.69, p =0.009). Multi-covariate Cox regression analysis indicated BAP1 was a significant predictor for overall survival after adjusting for age of diagnosis, presence of ulceration, Breslow depth and CM stages in patients older than 50 years but not in younger patients. Co-expression analysis revealed no shared genes in BAP1 altered UM and CM tumors, further supporting a completely distinctive role of BAP1 in CM and UM. Conclusions: low BAP1 mRNA was significantly associated with a better overall survival in CM patients, in sharp contrast to its tumor suppressor role in UM where low or loss of BAP1 indicated a worse overall survival. Function of BAP1 may be dependent on cellular context.

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Computational recognition of lncRNA signature of tumor-infiltrating B lymphocytes with potential implications in prognosis and immunotherapy of bladder cancer

Briefings in Bioinformatics ◽

10.1093/bib/bbaa047 ◽

2020 ◽

Cited By ~ 9

Author(s):

Meng Zhou ◽

Zicheng Zhang ◽

Siqi Bao ◽

Ping Hou ◽

Congcong Yan ◽

...

Keyword(s):

B Lymphocytes ◽

Noncoding Rna ◽

Immune Cell ◽

Functional Characterization ◽

Predictive Biomarkers ◽

Computational Framework ◽

Gene Markers ◽

Programmed Death ◽

Clinical Covariates ◽

Programmed Death 1

Abstract Long noncoding RNAs (lncRNAs) have been associated with cancer immunity regulation and the tumor microenvironment (TME). However, functions of lncRNAs of tumor-infiltrating B lymphocytes (TIL-Bs) and their clinical significance have not yet been fully elucidated. In the present study, a machine learning-based computational framework is presented for the identification of lncRNA signature of TIL-Bs (named ‘TILBlncSig’) through integrative analysis of immune, lncRNA and clinical profiles. The TILBlncSig comprising eight lncRNAs (TNRC6C-AS1, WASIR2, GUSBP11, OGFRP1, AC090515.2, PART1, MAFG-DT and LINC01184) was identified from the list of 141 B-cell-specific lncRNAs. The TILBlncSig was capable of distinguishing worse compared with improved survival outcomes across different independent patient datasets and was also independent of other clinical covariates. Functional characterization of TILBlncSig revealed it to be an indicator of infiltration of mononuclear immune cells (i.e. natural killer cells, B-cells and mast cells), and it was associated with hallmarks of cancer, as well as immunosuppressive phenotype. Furthermore, the TILBlncSig revealed predictive value for the survival outcome and immunotherapy response of patients with anti-programmed death-1 (PD-1) therapy and added significant predictive power to current immune checkpoint gene markers. The present study has highlighted the value of the TILBlncSig as an indicator of immune cell infiltration in the TME from a noncoding RNA perspective and strengthened the potential application of lncRNAs as predictive biomarkers of immunotherapy response, which warrants further investigation.

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

Journal of Clinical Medicine ◽

10.3390/jcm9020411 ◽

2020 ◽

Vol 9 (2) ◽

pp. 411 ◽

Cited By ~ 2

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.

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