An instance-specific causal framework for learning intercellular communication networks that define microenvironments of individual tumors

Cells within a tumor microenvironment (TME) dynamically communicate and influence each other's cellular states through an intercellular communication network (ICN). In cancers, intercellular communications underlie immune evasion mechanisms of individual tumors. We developed an instance-specific causal analysis framework for discovering tumor-specific ICNs. Using head and neck squamous cell carcinoma (HNSCC) tumors as a testbed, we first mined single-cell RNA-sequencing data to discover gene expression modules (GEMs) that reflect the states of transcriptomic processes within tumor and stromal single cells. By deconvoluting bulk transcriptomes of HNSCC tumors profiled by The Cancer Genome Atlas (TCGA), we estimated the activation states of these transcriptomic processes in individual tumors. Finally, we applied instance-specific causal network learning to discover an ICN within each tumor. Our results show that cellular states of cells in TMEs are coordinated through ICNs that enable multi-way communications among epithelial, fibroblast, endothelial, and immune cells. Further analyses of individual ICNs revealed structural patterns that were shared across subsets of tumors, leading to the discovery of 4 different subtypes of networks that underlie disparate TMEs of HNSCC. Patients with distinct TMEs exhibited significantly different clinical outcomes. Our results show that the capability of estimating instance-specific ICNs reveals heterogeneity of ICNs and sheds light on the importance of intercellular communication in impacting disease development and progression.

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Upgrading the Repertoire of miRNAs in Gastric Adenocarcinoma to Provide a New Resource for Biomarker Discovery

International Journal of Molecular Sciences ◽

10.3390/ijms20225697 ◽

2019 ◽

Vol 20 (22) ◽

pp. 5697 ◽

Cited By ~ 2

Author(s):

Michelle E. Pewarchuk ◽

Mateus C. Barros-Filho ◽

Brenda C. Minatel ◽

David E. Cohn ◽

Florian Guisier ◽

...

Keyword(s):

Gastric Adenocarcinoma ◽

Biomarker Discovery ◽

The Cancer Genome Atlas ◽

Small Rna Sequencing ◽

Sequencing Data ◽

Specific Expression ◽

Novel Mirna ◽

Cancer Genome Atlas ◽

Context Specific ◽

Independent Cohort

Recent studies have uncovered microRNAs (miRNAs) that have been overlooked in early genomic explorations, which show remarkable tissue- and context-specific expression. Here, we aim to identify and characterize previously unannotated miRNAs expressed in gastric adenocarcinoma (GA). Raw small RNA-sequencing data were analyzed using the miRMaster platform to predict and quantify previously unannotated miRNAs. A discovery cohort of 475 gastric samples (434 GA and 41 adjacent nonmalignant samples), collected by The Cancer Genome Atlas (TCGA), were evaluated. Candidate miRNAs were similarly assessed in an independent cohort of 25 gastric samples. We discovered 170 previously unannotated miRNA candidates expressed in gastric tissues. The expression of these novel miRNAs was highly specific to the gastric samples, 143 of which were significantly deregulated between tumor and nonmalignant contexts (p-adjusted < 0.05; fold change > 1.5). Multivariate survival analyses showed that the combined expression of one previously annotated miRNA and two novel miRNA candidates was significantly predictive of patient outcome. Further, the expression of these three miRNAs was able to stratify patients into three distinct prognostic groups (p = 0.00003). These novel miRNAs were also present in the independent cohort (43 sequences detected in both cohorts). Our findings uncover novel miRNA transcripts in gastric tissues that may have implications in the biology and management of gastric adenocarcinoma.

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Heme Biosynthesis mRNA Expression Signature: Towards a Novel Prognostic Biomarker in Patients with Diffusely Infiltrating Gliomas

Cancers ◽

10.3390/cancers13040662 ◽

2021 ◽

Vol 13 (4) ◽

pp. 662

Author(s):

Mario Mischkulnig ◽

Barbara Kiesel ◽

Daniela Lötsch ◽

Thomas Roetzer ◽

Martin Borkovec ◽

...

Keyword(s):

Overall Survival ◽

Mrna Expression ◽

Postoperative Management ◽

Heme Biosynthesis ◽

The Cancer Genome Atlas ◽

Sequencing Data ◽

Who Grade ◽

Expression Signature ◽

Cancer Genome Atlas ◽

The Impact

Diffusely infiltrating gliomas are characterized by a variable clinical course, and thus novel prognostic biomarkers are needed. The heme biosynthesis cycle constitutes a fundamental metabolic pathway and might play a crucial role in glioma biology. The aim of this study was thus to investigate the role of the heme biosynthesis mRNA expression signature on prognosis in a large glioma patient cohort. Glioma patients with available sequencing data on heme biosynthesis expression were retrieved from The Cancer Genome Atlas (TCGA). In each patient, the heme biosynthesis mRNA expression signature was calculated and categorized into low, medium, and high expression subgroups. Differences in progression-free and overall survival between these subgroups were investigated including a multivariate analysis correcting for WHO grade, tumor subtype, and patient age and sex. In a total of 693 patients, progression-free and overall survival showed a strictly monotonical decrease with increasing mRNA expression signature subgroups. In detail, median overall survival was 134.2 months in the low, 79.9 months in the intermediate, and 16.5 months in the high mRNA expression signature subgroups, respectively. The impact of mRNA expression signature on progression-free and overall survival was independent of the other analyzed prognostic factors. Our data indicate that the heme biosynthesis mRNA expression signature might serve as an additional novel prognostic marker in patients with diffusely infiltrating gliomas to optimize postoperative management.

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Effect of Different Expression of Immune-Related lncRNA on Colon Adenocarcinoma and Its Relation to Prognosis

BioMed Research International ◽

10.1155/2020/6942740 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Meiwei Mu ◽

Yi Tang ◽

Zheng Yang ◽

Yuling Qiu ◽

Xiaohong Li ◽

...

Keyword(s):

Cox Regression ◽

Colon Adenocarcinoma ◽

The Cancer Genome Atlas ◽

Risk Scores ◽

Future Research ◽

Sequencing Data ◽

Tissue Samples ◽

Gene Sets ◽

Cancer Genome Atlas ◽

Immune Related Genes

Objective. To explore the expression of immune-related lncRNAs in colon adenocarcinoma and find out the effect on how these lncRNAs influence the development and prognosis of colon adenocarcinoma. Method. Transcriptome data of colon adenocarcinoma from The Cancer Genome Atlas (TCGA) were downloaded, and gene sets “IMMUNE RESPONSE” and “IMMUNE SYSTEM PROCESS” were sought from the Molecular Signatures Database (MSigDB). The expression of immune-related genes was extracted that were immune-related mRNAs. Then, the immune-related lncRNAs were sought out by utilizing of the above data. Clinical traits were combined with immune-related lncRNAs, so that prognostic-related lncRNAs were identified by Cox regression. Multivariate Cox regression was built to calculate risk scores. Relationships between clinical traits and immune-related lncRNAs were also calculated. Result. A total of 480 colorectal adenocarcinoma patients and 41 normal control patients’ transcriptome sequencing data of tissue samples were obtained from TCGA database. 918 immune-related lncRNAs were screened. Cox regression showed that 34 immune-related lncRNAs were associated with colon adenocarcinoma prognosis. Seven lncRNAs were independent risk factors. Conclusion. This study revealed that some lncRNAs can affect the development and prognosis of colon adenocarcinoma. It may provide new theory evidence of molecular mechanism for the future research and molecular targeted therapy of colon adenocarcinoma.

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An R Package for Divergence Analysis of Omics Data

10.1101/720391 ◽

2019 ◽

Author(s):

Wikum Dinalankara ◽

Qian Ke ◽

Donald Geman ◽

Luigi Marchionni

Keyword(s):

High Throughput Sequencing ◽

R Package ◽

The Cancer Genome Atlas ◽

High Dimensional ◽

Omics Data ◽

Sequencing Data ◽

High Throughput Sequencing Data ◽

Ternary Code ◽

Cancer Genome Atlas ◽

Level Analysis

AbstractGiven the ever-increasing amount of high-dimensional and complex omics data becoming available, it is increasingly important to discover simple but effective methods of analysis. Divergence analysis transforms each entry of a high-dimensional omics profile into a digitized (binary or ternary) code based on the deviation of the entry from a given baseline population. This is a novel framework that is significantly different from existing omics data analysis methods: it allows digitization of continuous omics data at the univariate or multivariate level, facilitates sample level analysis, and is applicable on many different omics platforms. The divergence package, available on the R platform through the Bioconductor repository collection, provides easy-to-use functions for carrying out this transformation. Here we demonstrate how to use the package with sample high throughput sequencing data from the Cancer Genome Atlas.

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Genomic Landscape of Early-stage Colorectal Neoplasia Developing From the Ulcerative Colitis Mucosa in the Japanese Population

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa268 ◽

2020 ◽

Author(s):

Kenta Matsumoto ◽

Yuji Urabe ◽

Shiro Oka ◽

Katsuaki Inagaki ◽

Hidenori Tanaka ◽

...

Keyword(s):

Ulcerative Colitis ◽

Early Stage ◽

Colorectal Neoplasia ◽

Genomic Analysis ◽

The Cancer Genome Atlas ◽

Sequencing Data ◽

Kras Mutations ◽

Tp53 Mutations ◽

Amino Terminal ◽

Cancer Genome Atlas

Abstract Backgrounds Colorectal neoplasias (CRN)s developing from the ulcerative colitis (UC) mucosa include both colitic and sporadic neoplasias. Although several genomic analyses of advanced colitis-associated cancer are available, such studies do not distinguish between colitic and sporadic cases, and the early-stage genomic alterations involved in the onset of colitic cancer remain unclear. To address this, we performed a genomic analysis of early-stage CRN developing from the UC mucosa (CRNUC). Methods We extracted DNA from 36 early-stage CRNUCs (T1 cancer, 10; dysplasia, 26) from 32 UC patients and performed targeted sequencing of 43 genes commonly associated with colitis-associated cancer and compared the results with sequencing data from the Japanese invasive colitis-associated cancer. Results The most frequently mutated gene in the CRNUC cohort was APC (mutated in 47.2% of the cases), followed by TP53 (44.4%), KRAS (27.8%), and PRKDC (27.8%). None of the TP53 mutations occurred at any of the hotspot codons. Although the TP53 mutations in The Cancer Genome Atlas of Colorectal Cancer were dispersed throughout the gene, those detected here in CRNUC cases were concentrated in the amino terminal part of the DNA-binding domain. Interestingly, the mutations in KRAS and TP53 were mutually exclusive in CRNUC, and CRNUCs with KRAS mutations had histologically serrated lesions in the gland duct. Mayo endoscopic subscore was higher in TP53-mutated CRNUCs and lower in KRAS-mutated CRNUCs. Conclusions Our findings suggest that early-stage CRNUC can be classified into 2 groups: those developing through the carcinogenic pathway via TP53 mutations and those developing through the carcinogenic pathway via KRAS mutations.

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Transposable element expression in tumors is associated with immune infiltration and increased antigenicity

Nature Communications ◽

10.1038/s41467-019-13035-2 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 16

Author(s):

Yu Kong ◽

Christopher M. Rose ◽

Ashley A. Cass ◽

Alexander G. Williams ◽

Martine Darwish ◽

...

Keyword(s):

Dna Methylation ◽

De Novo ◽

Computational Method ◽

The Cancer Genome Atlas ◽

Potential Consequence ◽

Sequencing Data ◽

Antiviral Responses ◽

Genome Wide ◽

Cancer Genome Atlas ◽

Demethylation Agent

AbstractProfound global loss of DNA methylation is a hallmark of many cancers. One potential consequence of this is the reactivation of transposable elements (TEs) which could stimulate the immune system via cell-intrinsic antiviral responses. Here, we develop REdiscoverTE, a computational method for quantifying genome-wide TE expression in RNA sequencing data. Using The Cancer Genome Atlas database, we observe increased expression of over 400 TE subfamilies, of which 262 appear to result from a proximal loss of DNA methylation. The most recurrent TEs are among the evolutionarily youngest in the genome, predominantly expressed from intergenic loci, and associated with antiviral or DNA damage responses. Treatment of glioblastoma cells with a demethylation agent results in both increased TE expression and de novo presentation of TE-derived peptides on MHC class I molecules. Therapeutic reactivation of tumor-specific TEs may synergize with immunotherapy by inducing inflammation and the display of potentially immunogenic neoantigens.

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Hypoxic Roadmap of Glioblastoma—Learning about Directions and Distances in the Brain Tumor Environment

Cancers ◽

10.3390/cancers12051213 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1213 ◽

Cited By ~ 2

Author(s):

Agnieszka Bronisz ◽

Elżbieta Salińska ◽

E. Antonio Chiocca ◽

Jakub Godlewski

Keyword(s):

Brain Tumor ◽

Immune Escape ◽

Differential Expression Analysis ◽

Metabolic Stress ◽

The Cancer Genome Atlas ◽

Adaptation To Hypoxia ◽

Sequencing Data ◽

Immune Therapies ◽

Tumor Environment ◽

Cancer Genome Atlas

Malignant brain tumor—glioblastoma is not only difficult to treat but also hard to study and model. One of the reasons for these is their heterogeneity, i.e., individual tumors consisting of cancer cells that are unlike each other. Such diverse cells can thrive due to the simultaneous co-evolution of anatomic niches and adaption into zones with distorted homeostasis of oxygen. It dampens cytotoxic and immune therapies as the response depends on the cellular composition and its adaptation to hypoxia. We explored what transcriptome reposition strategies are used by cells in the different areas of the tumor. We created the hypoxic map by differential expression analysis between hypoxic and cellular features using RNA sequencing data cross-referenced with the tumor’s anatomic features (Ivy Glioblastoma Atlas Project). The molecular functions of genes differentially expressed in the hypoxic regions were analyzed by a systematic review of the gene ontology analysis. To put a hypoxic niche signature into a clinical context, we associated the model with patients’ survival datasets (The Cancer Genome Atlas). The most unique class of genes in the hypoxic area of the tumor was associated with the process of autophagy. Both hypoxic and cellular anatomic features were enriched in immune response genes whose, along with autophagy cluster genes, had the power to predict glioblastoma patient survival. Our analysis revealed that transcriptome responsive to hypoxia predicted worse patients’ outcomes by driving tumor cell adaptation to metabolic stress and immune escape.

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Extracellular Vesicles Orchestrate Immune and Tumor Interaction Networks

Cancers ◽

10.3390/cancers12123696 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3696

Author(s):

Kevin Ho Wai Yim ◽

Ala’a Al Hrout ◽

Simone Borgoni ◽

Richard Chahwan

Keyword(s):

Communication Networks ◽

Extracellular Vesicles ◽

Intercellular Communication ◽

Potential Role ◽

Viral Infections ◽

Biological Effects ◽

Surface Markers ◽

Physiological Conditions ◽

Intercellular Communications

Extracellular vesicles (EVs) are emerging as potent and intricate intercellular communication networks. From their first discovery almost forty years ago, several studies have bolstered our understanding of these nano-vesicular structures. EV subpopulations are now characterized by differences in size, surface markers, cargo, and biological effects. Studies have highlighted the importance of EVs in biology and intercellular communication, particularly during immune and tumor interactions. These responses can be equally mediated at the proteomic and epigenomic levels through surface markers or nucleic acid cargo signaling, respectively. Following the exponential growth of EV studies in recent years, we herein synthesize new aspects of the emerging immune–tumor EV-based intercellular communications. We also discuss the potential role of EVs in fundamental immunological processes under physiological conditions, viral infections, and tumorigenic conditions. Finally, we provide insights on the future prospects of immune–tumor EVs and suggest potential avenues for the use of EVs in diagnostics and therapeutics.

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Scalable Nonparametric Prescreening Method for Searching Higher-Order Genetic Interactions Underlying Quantitative Traits

Genetics ◽

10.1534/genetics.119.302658 ◽

2019 ◽

Vol 213 (4) ◽

pp. 1209-1224 ◽

Cited By ~ 2

Author(s):

Juho A. J. Kontio ◽

Mikko J. Sillanpää

Keyword(s):

High Throughput ◽

High Throughput Sequencing ◽

Real Data ◽

Higher Order ◽

The Cancer Genome Atlas ◽

Sequencing Data ◽

High Throughput Sequencing Data ◽

Automatic Relevance Determination ◽

Cancer Genome Atlas ◽

Low Dimensional

Gaussian process (GP)-based automatic relevance determination (ARD) is known to be an efficient technique for identifying determinants of gene-by-gene interactions important to trait variation. However, the estimation of GP models is feasible only for low-dimensional datasets (∼200 variables), which severely limits application of the GP-based ARD method for high-throughput sequencing data. In this paper, we provide a nonparametric prescreening method that preserves virtually all the major benefits of the GP-based ARD method and extends its scalability to the typical high-dimensional datasets used in practice. In several simulated test scenarios, the proposed method compared favorably with existing nonparametric dimension reduction/prescreening methods suitable for higher-order interaction searches. As a real-data example, the proposed method was applied to a high-throughput dataset downloaded from the cancer genome atlas (TCGA) with measured expression levels of 16,976 genes (after preprocessing) from patients diagnosed with acute myeloid leukemia.

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