scholarly journals Computational Tumor Infiltration Phenotypes Enable the Spatial and Genomic Analysis of Immune Infiltration in Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Henrik Failmezger ◽  
Natalie Zwing ◽  
Achim Tresch ◽  
Konstanty Korski ◽  
Fabian Schmich
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Computational Method ◽  
The Cancer Genome Atlas ◽  
Point Pattern Analysis ◽  
Point Pattern ◽  
Base Line ◽  
Tumor Infiltration ◽  
Durable Response ◽  
Immune Infiltration

Cancer immunotherapy has led to significant therapeutic progress in the treatment of metastatic and formerly untreatable tumors. However, drug response rates are variable and often only a subgroup of patients will show durable response to a treatment. Biomarkers that help to select those patients that will benefit the most from immunotherapy are thus of crucial importance. Here, we aim to identify such biomarkers by investigating the tumor microenvironment, i.e., the interplay between different cell types like immune cells, stromal cells and malignant cells within the tumor and developed a computational method that determines spatial tumor infiltration phenotypes. Our method is based on spatial point pattern analysis of immunohistochemically stained colorectal cancer tumor tissue and accounts for the intra-tumor heterogeneity of immune infiltration. We show that, compared to base-line models, tumor infiltration phenotypes provide significant additional support for the prediction of established biomarkers in a colorectal cancer patient cohort (n = 80). Integration of tumor infiltration phenotypes with genetic and genomic data from the same patients furthermore revealed significant associations between spatial infiltration patterns and common mutations in colorectal cancer and gene expression signatures. Based on these associations, we computed novel gene signatures that allow one to predict spatial tumor infiltration patterns from gene expression data only and validated this approach in a separate dataset from the Cancer Genome Atlas.

scholarly journals Interferon regulatory factor family influences tumor immunity and prognosis of patients with colorectal cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yan-Jie Chen ◽  
Shu-Neng Luo ◽  
Ling Dong ◽  
Tao-Tao Liu ◽  
Xi-Zhong Shen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Noncoding Rna ◽  
Immune Cell ◽  
Family Members ◽  
Interferon Regulatory Factor ◽  
The Cancer Genome Atlas ◽  
Regulatory Factor ◽  
Clinical Prognosis ◽  
Immune Infiltration

Abstract Background Since interferon regulatory factor (IRF) family functions in immune response to viral infection, its role in colorectal cancer (CRC) has not been inspected before. This study tries to investigate members of IRF family using bioinformatics approaches in aspect of differential expressions, biological function, tumor immune infiltration and clinical prognostic value for patients with CRC. Methods Transcriptome profiles data, somatic mutations and clinical information of CRC were obtained from COAD/READ dataset of The Cancer Genome Atlas (TCGA) as a training set. Gene expression data (GSE17536 and GSE39582) were downloaded from the Gene Expression Omnibus as a validating set. A random forest algorithm was used to score the risk for every case. Analyzing gene and function enrichment, constructing protein–protein interaction and noncoding RNA network, identifying hub-gene, characterizing tumor immune infiltration, evaluating differences in tumor mutational burden (TMB) and sensitivity to chemotherapeutics or immunotherapy were performed by a series of online tools and R packages. Immunohistochemical (IHC) examinations were carried out validation in tissue samples. Results Principal-component analysis (PCA) suggested that the transcript expression levels of nine members of IRF family differed between normal colorectum and CRC. The risk score constructed by IRF family not only acted as an independent factor for predicting survival in CRC patients with different biological processes, signaling pathways and TMB, but also indicated different immunotherapy response with diverse immune and stromal cells infiltration. IRF3 and IRF7 were upregulated in CRC and suggested a shorter survival time in patients with CRC. Differentially expressed members of IRF family exhibited varying degrees of immune cell infiltration. IHC analysis showed a positive association between IRF3 and IRF7 expression and tumor-infiltrating immune cells, including CD4+ T cell and CD68+ macrophages. Conclusions On account of differential expression, IRF family members can help to predict both response to immunotherapy and clinical prognosis of patients with CRC. Our bioinformatic investigation not only gives a preliminary picture of the genetic features as well as tumor microenvironment, but it may provide a clue for further experimental exploration and verification on IRF family members in CRC.

scholarly journals Profiles of immune infiltration in colorectal cancer and their clinical significant: A gene expression‐based study

2018 ◽  
Vol 7 (9) ◽  
pp. 4496-4508 ◽  
Author(s):  
Yongfu Xiong ◽  
Kang Wang ◽  
He Zhou ◽  
Linglong Peng ◽  
Wenxian You ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Immune Infiltration

Regulation of gene expression by DNA methylation with cytotoxic T lymphocytes evaluation in consensus molecular subtypes of colorectal cancer.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 25-25
Author(s):  
Yuanyuan Shen ◽  
Justin Hummel ◽  
Isabel Cristina Trindade ◽  
Christos Papageorgiou ◽  
Chi-Ren Shyu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Dna Methylation ◽  
Molecular Subtypes ◽  
Epigenetic Modification ◽  
Pearson Correlation ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
The Cancer Genome Atlas ◽  
Highly Correlated

25 Background: Low cytotoxic T lymphocyte (CTLs) infiltration in colorectal cancer (CRC) tumors is a challenge to treatment with immune checkpoint inhibitors. Consensus molecular subtypes (CMS) classify patients based on tumor attributes, and CMS1 patients include the majority of patients with high CTL infiltration and “inflamed” tumors. Epigenetic modification plays a critical role in gene expression and therapy resistance. Therefore, in this study we compared DNA methylation, gene expression, and CTL infiltration of CMS1 patients to other CMS groups to determine targets for improving immunotherapy in CRC. Methods: RNA-seq (n = 511) and DNA methylation (n = 316) from The Cancer Genome Atlas databases were used to determine gene expression and methylation profiles based on CMSs. CMS1 was used as a reference and compared to other subtypes (CMS2-4). Microenvironment Cell Populations- counter (MCPcounter) was used to determine tumor CTL infiltration. Genes with significantly different expression (p < 0.01, LogFC≥|1.5|) and difference of mean methylation β value ≥|0.25| were integrated for Pearson correlation coefficient analysis with MCPcounter score (r > |0.7|). Results: Comparing CMS1 and CMS2, ARHGAP9, TBX21, and LAG3 were differentially methylated and correlated with CTL scores. ARHGAP9 and TBX21 were decreased and hypomethylated in CMS2. Comparing CMS1 and CMS3, ARHGAP9, TBX21, FMNL1, HLA-DPB1, and STX11 were downregulated in CMS3 and highly correlated with CTL scores. ARHGAP9, FMNL1, HLA-DPB1, and STX11 were hypomethylated in CMS3 and TBX21 was methylated in both, but had a higher methylation ratio in CMS1. Comparing CMS1 and CMS4, TBX21 was the only gene downregulated, hypomethylated, and highly correlated with CTL scores in CMS4 patients. Conclusions: We found six genes differentially expressed, differentially methylated, and highly correlated with CTL infiltration when comparing CMS1 to other CMS groups. Specifically, TBX21 was the only gene highly correlated with CTL scores with differential gene expression and methylation in CMS2-4 when compared to CMS1. Thus, T-bet may be a critical regulator of T cell responses in CRC.

scholarly journals A comprehensive analysis of the microbiota composition and gene expression in colorectal cancer

2019 ◽  
Author(s):  
Qian Zhang ◽  
Huan Zhao ◽  
Dedong Wu ◽  
Dayong Cao ◽  
Wang Ma
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Gut Microbiota ◽  
Bile Secretion ◽  
Colorectal Carcinogenesis ◽  
The Cancer Genome Atlas ◽  
Rrna Gene ◽  
Microbiota Composition ◽  
Sequencing Data ◽  
Keywords Colorectal Cancer

Abstract Subject: The dysbiosis of gut microbiota is pivotal in colorectal carcinogenesis. However, the synergy between an altered gut microbiota composition and differential gene expression of specific genes in colorectal cancer (CRC) remains elusive. Method: The gut microbiota dataset with number SRP158779, which contained 19 CRC samples and 19 normal samples, was downloaded from the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) database. The 16S rRNA gene sequences from this dataset were clustered into operational taxonomic units (OTUs); thereafter, the OTUs that were differentially enriched in CRC were identified and classified, followed by prediction of their functions. Additionally, RNA sequencing data from CRC samples was obtained from The Cancer Genome Atlas project (TCGA), and the differentially expressed genes (DEGs) and enriched pathways were identified. Finally, similar pathways that were significantly enriched in both differential OTUs and DEGs were screened. Key genes related to these pathways were executed the prognosis analysis. Results: The presence of Proteobacteria and Fusobacteria increased considerably in CRC samples; conversely, the abundance of Firmicute and Spirochaetes decreased markedly. In particular, the genera Fusobacterium , Catenibacterium , and Shewanella were detectable in tumor samples. Moreover, 246 DEGs were identified between tumor and normal tissues. Both DEGs and microbiota were involved in bile secretion and steroid hormone biosynthesis pathways. Finally, CYP3A4 and ABCG2 expression in CRC was related to the prognostic outcomes of CRC patients. Conclusion: Identifying the complicated interplay between gut microbiota and the DEGs could help in further understanding the pathogenesis of CRC, and these findings would enable better diagnosis and treatment of CRC patients. Keywords: colorectal cancer, gut microflora, gene expression, pathways enrichment, survival analysis

scholarly journals Effects of Hypoxia in Intestinal Tumors on Immune Cell Behavior in the Tumor Microenvironment

2020 ◽  
Author(s):  
Luping Zhang ◽  
Shaokun Wang ◽  
Yachen Wang ◽  
Weidan Zhao ◽  
Yingli Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Risk Score ◽  
Immune Cell ◽  
Risk Groups ◽  
Low Risk ◽  
Computational Method ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cell Behavior

Abstract Background: Imbalanced nutritional supply and demand in the tumor microenvironment often leads to hypoxia. The subtle interaction between hypoxia and immune cell behavior plays an important role in tumor occurrence and development. However, the functional relationship between hypoxia and the tumor microenvironment remains unclear. Therefore, we aimed to investigate the effect of hypoxia on the intestinal tumor microenvironment.Method: We extracted the names of hypoxia-related genes from the Gene Set Enrichment Analysis (GSEA) database and screened them for those associated with the prognosis of colorectal cancer, with the final list including ALDOB, GPC1, ALDOC, and SLC2A3. Using the sum of the expression levels of these four genes, provided by The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and the expression coefficients, we developed a hypoxia risk score model. Using the median risk score value, we divided the patients in the two databases into high- and low-risk groups.GSEA was used to compare the enrichment differences between the two groups.We used the CIBERSORT computational method to analyze immune cell infiltration.Finally,the correlation between these five genes and hypoxia was analyzed. Result: The prognosis of the two groups differed significantly, with a higher survival rate in the low-risk group than in the high-risk group.We found that the different risk groups were enriched by immune-related and inflammatory pathways. We identified activated CD4 memory T cells and M0 macrophages in TCGA and GEO databases and found that CCL2/4/5, CSF1, and CX3CL1 contributed toward the increased infiltration rate of these immune cell types. Finally, we observed a positive correlation between the five candidate genes’ expression and the risk of hypoxia, with significant differences in the level of expression of each of these genes between patient risk groups.Conclusion: Overall, our data suggest that hypoxia is associated with the prognosis and rate of immune system infiltration in patients with colorectal cancer. This finding may improve immunotherapy for colorectal cancer.

scholarly journals Potential Biomarkers of Colon Adenocarcinoma Based on Weighted Gene Co-Expression Network Analysis

2021 ◽  
Author(s):  
Zhongze Cui ◽  
Shuang He ◽  
Feifei Wen ◽  
Xiaoyang Xu ◽  
Yangyang Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Colon Cancer ◽  
Network Analysis ◽  
Expression Profiles ◽  
Differential Expression Analysis ◽  
Colon Adenocarcinoma ◽  
The Cancer Genome Atlas ◽  
Future Research ◽  
Related Gene

Abstract Background: Colon adenocarcinoma (COAD) is one of the most common malignancies worldwide. Although a large number of studies have elucidated the aetiology of colorectal cancer, the exact mechanism of colorectal cancer development remains to be determined.To identify key modules and prognostic genes that may be involved in the occurrence and development of COAD, weighted gene coexpression network analysis (WGCNA) and differential expression analysis were performed on datasets GSE41657 and GSE74602 from the Gene Expression Omnibus (GEO) database to screen for prognostic differentially expressed genes. Gene expression profiles and clinical information were collected from The Cancer Genome Atlas (TCGA) database for verification.Results: Through WGCNA and DEGs analysis, 439 genes in key functional modules were obtained, and 26 prognostic related genes were finally obtained through prognostic analysis: (1) We screened 5 genes（RPP40, DUSP18, PPRC1, MFSD11 and PDCD11） that have not been studied in COAD.（2）We obtained the most critical module in the occurrence and development of colon cancer and obtained one prognosis-related gene, NUP85, from the most critical module.The relationship between it and tumor immune microenvironment was verified.（3） A prognostic model comprising four coexpressed differential genes was constructed; TIMP1, PMM2, E2F3 and MORC2 were selected as the key prognosis-related genes.Conclusions: （1）As new biomarkers，prognostic genes RPP40, DUSP18, PPRC1, MFSD11 and PDCD11 may be potential therapeutic targets for COAD, and provide new ideas for future research on the mechanism of COAD. （2）NUP85 may be an immune-related gene which was negatively correlated with CD4+ T cell and M2 macrophagesthat plays an important role in inhibiting the occurrence and development of colorectal adenocarcinoma. （3）A Cox proportional risk model based on gene expression can be used to predict the prognosis and survival time of patients with colon cancer.

scholarly journals EVI2B Is a New Prognostic Biomarker in Metastatic Melanoma with IFNgamma Associated Immune Infiltration

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4110
Author(s):  
Satoru Yonekura ◽  
Kosuke Ueda
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Metastatic Melanoma ◽  
Prognostic Biomarker ◽  
Integration Site ◽  
Tumor Infiltrating Lymphocytes ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Immune Infiltration ◽  
Ifn Γ

Background: To assess the prognostic role and the antitumor immunological relevance of ecotropic viral integration site 2B (EVI2B) in metastatic melanoma. Methods: In this study, we integrated clinical data, mRNA expression data, and the distribution and fraction of tumor infiltrating lymphocytes (TILs) using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets (GSE65904 and GSE19234). Results: The univariate and multivariate analyses showed that higher gene expression of EVI2B was significantly associated with longer prognoses. The EVI2B-high melanoma tissue had favorable histological parameters such as a brisk global distribution pattern and clustering structure of TILs (i.e., Banfield and Raftery index) with enriched CD8+ T cells over regulatory T cells and increased cytotoxicity scores. In addition, EVI2B expression positively correlated with IFN-γ signature genes (CXCL10, CXCL9, HLA-DRA, IDO1, IFNG, and STAT1) and other various immunomodulatory genes. Conclusion: EVI2B is a novel prognostic biomarker with IFN-γ associated immune infiltration in metastatic melanoma.

scholarly journals Identification of Novel Survival Related lncRNA-miRNA-mRNA Competing Endogenous RNA Network Associated with Immune Infiltration in Colorectal Cancer

2020 ◽  
Author(s):  
Jianxin Li ◽  
Ting Han ◽  
Xin Wang ◽  
Yinchun Wang ◽  
Qingqiang Yang
Keyword(s):  
Colorectal Cancer ◽  
Regulatory Network ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Immune Checkpoints ◽  
Competing Endogenous Rna ◽  
Expression Levels ◽  
Go Annotation ◽  
Immune Infiltration ◽  
Cerna Network

Abstract Background: Increasing studies have reported that long noncoding RNAs (lncRNAs) play critical roles in the initiation and progression of carcinogenesis. However, the underlying regulatory mechanisms of lncRNA related competing endogenous RNA (ceRNA) network in colorectal cancer (CRC) are not fully understood.Methods: Dysregulated microRNAs (miRNAs) in CRC samples were screened from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database. After that, the key miRNAs were filtered out through a comprehensive assessment of their expression levels and prognostic values. Subsequently, the targeted downstream mRNAs and upstream lncRNAs of the key miRNAs were predicted by using multiple bioinformatic databases. A ceRNA network was constructed by using Cytoscape, and the Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on this network using the DAVID database. Ultimately, expression levels and prognostic values of the lncRNAs and mRNAs were evaluated, and a survival related ceRNA network was constructed and visualized by using Cytoscape. In addition, the Gene Set Enrichment Analysis (GSEA) software package was employed to identify the pathways in which this survival related ceRNA network was enriched. Furthermore, correlations of ceRNA network with immune infiltration level were estimated by the Tumor Immune Estimation Resource (TIMER) databases.Results: In total, 28 dysregulated miRNAs were obtained, and two of them were identified as key miRNAs based on expression levels and prognostic values analyses. Subsequently, a total of three upstream lncRNAs and 309 downstream mRNAs were predicted by using bioinformatic tools, and two key lncRNAs and eight key mRNAs were identified by expression and survival analysis. A ceRNA regulatory network associated with the prognosis of CRC patients was constructed. Furthermore, GSEA analysis indicated the possible association of key mRNAs with CRC onset and progression. Importantly, immune infiltration analysis revealed that the ceRNA network was remarkably associated with infiltration abundance of multiple immune cells and expression levels of immune checkpoints.Conclusions: We constructed a survival related ceRNA regulatory network in human CRC, NEAT1 and XIST are potential prognostic factors that affect CRC onset and progression by targeting miR-195-5p.

scholarly journals Identification of Key Prognostic Biomarker and Its Correlation with Immune Infiltrates in Pancreatic Ductal Adenocarcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Hong Luan ◽  
Chuang Zhang ◽  
Tuo Zhang ◽  
Ye He ◽  
Yanna Su ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Poor Prognosis ◽  
Immune Therapy ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Immune Checkpoints ◽  
Hub Genes ◽  
Immune Infiltration ◽  
The Relationship

Pancreatic ductal adenocarcinoma (PDAC) is an extremely malignant tumor. The immune profile of PDAC and the immunologic milieu of its tumor microenvironment (TME) are unique; however, the mechanism of how the TME engineers the carcinogenesis of PDAC is not fully understood. This study is aimed at better understanding the relationship between the immune infiltration of the TME and gene expression and identifying potential prognostic and immunotherapeutic biomarkers for PDAC. Analysis of data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases identified differentially expressed genes (DEGs), including 159 upregulated and 53 downregulated genes. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes enrichment were performed and showed that the DEGs were mainly enriched for the PI3K-Akt signaling pathway and extracellular matrix organization. We used the cytoHubba plugin of Cytoscape to screen out the most significant ten hub genes by four different models (Degree, MCC, DMNC, and MNC). The expression and clinical relevance of these ten hub genes were validated using Gene Expression Profiling Interactive Analysis (GEPIA) and the Human Protein Atlas, respectively. High expression of nine of the hub genes was positively correlated with poor prognosis. Finally, the relationship between these hub genes and tumor immunity was analyzed using the Tumor Immune Estimation Resource. We found that the expression of SPARC, COL6A3, and FBN1 correlated positively with infiltration levels of six immune cells in the tumors. In addition, these three genes had a strong coexpression relationship with the immune checkpoints. In conclusion, our results suggest that nine upregulated biomarkers are related to poor prognosis in PDAC and may serve as potential prognostic biomarkers for PDAC therapy. Furthermore, SPARC, COL6A3, and FBN1 play an important role in tumor-related immune infiltration and may be ideal targets for immune therapy against PDAC.

scholarly journals Comprehensive analysis of ceRNA networks reveals prognostic lncRNAs related to immune infiltration in colorectal cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jingyi Chen ◽  
Yuxuan Song ◽  
Mei Li ◽  
Yu Zhang ◽  
Tingru Lin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Target Genes ◽  
Immune Cell ◽  
Pearson Correlation ◽  
Enrichment Analysis ◽  
Cell Types ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cerna Network

Abstract Background Competing endogenous RNA (ceRNA) represents a class of RNAs (e.g., long noncoding RNAs [lncRNAs]) with microRNA (miRNA) binding sites, which can competitively bind miRNA and inhibit its regulation of target genes. Increasing evidence has underscored the involvement of dysregulated ceRNA networks in the occurrence and progression of colorectal cancer (CRC). The purpose of this study was to construct a ceRNA network related to the prognosis of CRC and further explore the potential mechanisms that affect this prognosis. Methods RNA-Seq and miRNA-Seq data from The Cancer Genome Atlas (TCGA) were used to identify differentially expressed lncRNAs (DElncRNAs), microRNAs (DEmiRNAs), and mRNAs (DEmRNAs), and a prognosis-related ceRNA network was constructed based on DElncRNA survival analysis. Subsequently, pathway enrichment, Pearson correlation, and Gene Set Enrichment Analysis (GSEA) were performed to determine the function of the genes in the ceRNA network. Gene Expression Profiling Interactive Analysis (GEPIA) and immunohistochemistry (IHC) were also used to validate differential gene expression. Finally, the correlation between lncRNA and immune cell infiltration in the tumor microenvironment was evaluated based on the CIBERSORT algorithm. Results A prognostic ceRNA network was constructed with eleven key survival-related DElncRNAs (MIR4435-2HG, NKILA, AFAP1-AS1, ELFN1-AS1, AC005520.2, AC245884.8, AL354836.1, AL355987.4, AL591845.1, LINC02038, and AC104823.1), 54 DEmiRNAs, and 308 DEmRNAs. The MIR4435-2HG- and ELFN1-AS1-associated ceRNA subnetworks affected and regulated the expression of the COL5A2, LOX, OSBPL3, PLAU, VCAN, SRM, and E2F1 target genes and were found to be related to prognosis and tumor-infiltrating immune cell types. Conclusions MIR4435-2HG and ELFN1-AS1 are associated with prognosis and tumor-infiltrating immune cell types and could represent potential prognostic biomarkers or therapeutic targets in colorectal carcinoma.

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