scholarly journals Gene set enrichment analysis: A genome-wide expression profile-based strategy for discovering functional microRNA–disease relationships

2017 ◽  
Vol 46 (2) ◽  
pp. 596-611 ◽  
Author(s):  
Yin Ni ◽  
Caiyun Song ◽  
Shuqing Jin ◽  
Zhoufeng Chen ◽  
Ming Ni ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Pattern Matching ◽  
Expression Profile ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Gene Set Enrichment ◽  
Genome Wide ◽  
A Genome ◽  
Matching Strategy ◽  
Genome Wide Expression

Objective To explore stable and functional microRNA (miRNA)–disease relationships using a genome-wide expression profile pattern matching strategy. Methods We applied the ranked microarray pattern matching strategy Gene Set Enrichment Analysis to identify miRNA permutations with similar expression patterns to diseases. We also used quantitative reverse transcription PCR to validate the predicted expression levels of miRNAs in three diseases: inflammatory bowel disease (IBD), oesophageal cancer, and colorectal cancer. Results We found that hsa-miR-200 c was upregulated more than 40-fold in oesophageal cancer. The expression of miR-16 and miR-124 was not consistently upregulated in IBD or colorectal cancer. Conclusions Our results suggest that this expression profile matching strategy can be used to identify functional miRNA–disease relationships.

scholarly journals Deficiency of 15-LOX-1 Induces Radioresistance through Downregulation of MacroH2A2 in Colorectal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1776 ◽  
Author(s):  
Yoo Jin Na ◽  
Bo Ram Kim ◽  
Jung Lim Kim ◽  
Sanghee Kang ◽  
Yoon A. Jeong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Specific Treatment ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Patient Specific ◽  
Histone H2a ◽  
Gene Set Enrichment ◽  
Damage Response ◽  
Radiation Induced

Despite the importance of radiation therapy, there are few radiation-related markers available for use in clinical practice. A larger catalog of such biomarkers is required to help clinicians decide when radiotherapy should be replaced with a patient-specific treatment. Arachidonate 15-lipoxygenase (15-LOX-1) enzyme is involved in polyunsaturated fatty acid metabolism. When colorectal cancer (CRC) cells were exposed to radiation, 15-LOX-1 was upregulated. To verify whether 15-LOX-1 protects against or induces DNA damage, we irradiated sh15-LOX-1 stable cells. We found that low 15-LOX-1 is correlated with radioresistance in CRC cells. These data suggest that the presence of 15-LOX-1 can be used as a marker for radiation-induced DNA damage. Consistent with this observation, gene-set-enrichment analysis based on microarray experiments showed that UV_RESPONSE was decreased in sh15-LOX-1 cells compared to shCon cells. Moreover, we discovered that the expression of the histone H2A variant macroH2A2 was sevenfold lower in sh15-LOX-1 cells. Overall, our findings present mechanistic evidence that macroH2A2 is transcriptionally regulated by 15-LOX-1 and suppresses the DNA damage response in irradiated cells by delaying H2AX activation.

scholarly journals Genome-wide association analysis of hippocampal volume identifies enrichment of neurogenesis-related pathways

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Emrin Horgusluoglu-Moloch ◽  
◽  
Shannon L. Risacher ◽  
Paul K. Crane ◽  
Derrek Hibar ◽  
...  
Keyword(s):  
Association Analysis ◽  
Adult Neurogenesis ◽  
Enrichment Analysis ◽  
Hippocampal Volume ◽  
Imaging Genetics ◽  
Gene Set Enrichment Analysis ◽  
Genome Wide Association ◽  
Gene Set Enrichment ◽  
Gene Set ◽  
Genome Wide

Abstract Adult neurogenesis occurs in the dentate gyrus of the hippocampus during adulthood and contributes to sustaining the hippocampal formation. To investigate whether neurogenesis-related pathways are associated with hippocampal volume, we performed gene-set enrichment analysis using summary statistics from a large-scale genome-wide association study (N = 13,163) of hippocampal volume from the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium and two year hippocampal volume changes from baseline in cognitively normal individuals from Alzheimer’s Disease Neuroimaging Initiative Cohort (ADNI). Gene-set enrichment analysis of hippocampal volume identified 44 significantly enriched biological pathways (FDR corrected p-value < 0.05), of which 38 pathways were related to neurogenesis-related processes including neurogenesis, generation of new neurons, neuronal development, and neuronal migration and differentiation. For genes highly represented in the significantly enriched neurogenesis-related pathways, gene-based association analysis identified TESC, ACVR1, MSRB3, and DPP4 as significantly associated with hippocampal volume. Furthermore, co-expression network-based functional analysis of gene expression data in the hippocampal subfields, CA1 and CA3, from 32 normal controls showed that distinct co-expression modules were mostly enriched in neurogenesis related pathways. Our results suggest that neurogenesis-related pathways may be enriched for hippocampal volume and that hippocampal volume may serve as a potential phenotype for the investigation of human adult neurogenesis.

scholarly journals Genome-Wide Association Study of Postoperative Cognitive Dysfunction in Older Surgical Patients

2020 ◽  
Author(s):  
Marc Rickenbacher ◽  
Céline S Reinbold ◽  
Stefan Herms ◽  
Per Hoffmann ◽  
Sven Cichon ◽  
...  
Keyword(s):  
Association Study ◽  
Candidate Genes ◽  
Cognitive Dysfunction ◽  
Genome Wide Association Study ◽  
Postoperative Cognitive Dysfunction ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

Abstract Background: Postoperative cognitive dysfunction (POCD) is a common neurocognitive complication after surgery and anesthesia, particularly in elderly patients. Various studies have suggested genetic risk factors for POCD. The study aimed to detect genome-wide associations of POCD in older patients.Methods: In this prospective observational cohort study, participants aged ≥65 years completed a set of neuropsychological tests before, at 1 week, and 3 months after major noncardiac surgery. Test variables were converted into standard scores (z-scores) based on demographic characteristics. POCD was diagnosed if the decline was >1 standard deviation in ≥2 of the 15 variables in the assessment battery. A genome-wide association study (GWAS) was performed to determine potential alleles that are linked to the POCD phenotype. In addition, candidate genes for POCD were identified in a literature search for further analysis.Results: Sixty-three patients with blood samples were included in the study. POCD was diagnosed in 47.6% of patients at 1 week and in 34.2% of patients at 3 months after surgery. Insufficient sample quality led to exclusion of 26 patients. In the remaining 37 patients, a GWAS was performed, but no association (P < 5*10-8) with POCD was found. The subsequent gene set enrichment analysis of 34 candidate genes did not reveal any significant associations.Conclusion: In this patient cohort, a GWAS did not reveal an association between specific genetic alleles and POCD at 1 week and 3 months after surgery. Future genetic analysis should focus on specific candidate genes for POCD.Trial registration: ClinicalTrials.gov (NCT02864173)

scholarly journals Importance of SNP Dependency Correction and Association Integration for Gene Set Analysis in Genome-Wide Association Studies

2021 ◽  
Vol 12 ◽  
Author(s):  
Michal Marczyk ◽  
Agnieszka Macioszek ◽  
Joanna Tobiasz ◽  
Joanna Polanska ◽  
Joanna Zyla
Keyword(s):  
Association Studies ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Genome Wide Association ◽  
Gene Set Analysis ◽  
Genome Wide Association Studies ◽  
Gene Set Enrichment ◽  
Gene Set ◽  
Genome Wide ◽  
The Impact

A typical genome-wide association study (GWAS) analyzes millions of single-nucleotide polymorphisms (SNPs), several of which are in a region of the same gene. To conduct gene set analysis (GSA), information from SNPs needs to be unified at the gene level. A widely used practice is to use only the most relevant SNP per gene; however, there are other methods of integration that could be applied here. Also, the problem of nonrandom association of alleles at two or more loci is often neglected. Here, we tested the impact of incorporation of different integrations and linkage disequilibrium (LD) correction on the performance of several GSA methods. Matched normal and breast cancer samples from The Cancer Genome Atlas database were used to evaluate the performance of six GSA algorithms: Coincident Extreme Ranks in Numerical Observations (CERNO), Gene Set Enrichment Analysis (GSEA), GSEA-SNP, improved GSEA for GWAS (i-GSEA4GWAS), Meta-Analysis Gene-set Enrichment of variaNT Associations (MAGENTA), and Over-Representation Analysis (ORA). Association of SNPs to phenotype was calculated using modified McNemar’s test. Results for SNPs mapped to the same gene were integrated using Fisher and Stouffer methods and compared with the minimum p-value method. Four common measures were used to quantify the performance of all combinations of methods. Results of GSA analysis on GWAS were compared to the one performed on gene expression data. Comparing all evaluation metrics across different GSA algorithms, integrations, and LD correction, we highlighted CERNO, and MAGENTA with Stouffer as the most efficient. Applying LD correction increased prioritization and specificity of enrichment outcomes for all tested algorithms. When Fisher or Stouffer were used with LD, sensitivity and reproducibility were also better. Using any integration method was beneficial in comparison with a minimum p-value method in specific combinations. The correlation between GSA results from genomic and transcriptomic level was the highest when Stouffer integration was combined with LD correction. We thoroughly evaluated different approaches to GSA in GWAS in terms of performance to guide others to select the most effective combinations. We showed that LD correction and Stouffer integration could increase the performance of enrichment analysis and encourage the usage of these techniques.

scholarly journals In vivo CRISPR/Cas9 knockout screen: TCEAL1 silencing enhances docetaxel efficacy in prostate cancer

2020 ◽  
Vol 3 (12) ◽  
pp. e202000770 ◽  
Author(s):  
Linda K Rushworth ◽  
Victoria Harle ◽  
Peter Repiscak ◽  
William Clark ◽  
Robin Shaw ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Elongation Factor ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Genome Wide ◽  
A Genome ◽  
Docetaxel Treatment ◽  
Crispr Screen ◽  
Altered Cell

Docetaxel chemotherapy in metastatic prostate cancer offers only a modest survival benefit because of emerging resistance. To identify candidate therapeutic gene targets, we applied a murine prostate cancer orthograft model that recapitulates clinical invasive prostate cancer in a genome-wide CRISPR/Cas9 screen under docetaxel treatment pressure. We identified 17 candidate genes whose suppression may enhance the efficacy of docetaxel, with transcription elongation factor A–like 1 (Tceal1) as the top candidate. TCEAL1 function is not fully characterised; it may modulate transcription in a promoter dependent fashion. Suppressed TCEAL1 expression in multiple human prostate cancer cell lines enhanced therapeutic response to docetaxel. Based on gene set enrichment analysis from transcriptomic data and flow cytometry, we confirmed that loss of TCEAL1 in combination with docetaxel leads to an altered cell cycle profile compared with docetaxel alone, with increased subG1 cell death and increased polyploidy. Here, we report the first in vivo genome-wide treatment sensitisation CRISPR screen in prostate cancer, and present proof of concept data on TCEAL1 as a candidate for a combinational strategy with the use of docetaxel.

scholarly journals Identification of a Hypoxia - Related lncRNA Signature For The Prognosis of Colorectal Cancer

2021 ◽  
Author(s):  
HUA HUANG ◽  
Shanshan Xu ◽  
Youran Li ◽  
Yunfei Gu ◽  
Lijiang Ji
Keyword(s):  
Colorectal Cancer ◽  
Roc Analysis ◽  
Cox Regression ◽  
Differential Expression Analysis ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Receptor Interaction ◽  
Prognostic Signature ◽  
Gene Set Enrichment ◽  
Gene Set

Abstract Background: Colorectal cancer (CRC), the commonly seen malignancy, ranks the 3rd place among the causes of cancer-associated mortality. As suggested by more and more studies, long coding RNAs (lncRNAs) have been considered as prognostic biomarkers for CRC. But the significance of hypoxic lncRNAs in predicting CRC prognosis remains unclear.Methods: The gene expressed profiles for CRC cases were obtained based on the Cancer Genome Atlas (TCGA) and applied to estimate the hypoxia score using a single-sample gene set enrichment analysis (ssGSEA) algorithm. Overall survival (OS) of high- and low-hypoxia score group was analyzed by the Kaplan–Meier (KM) plot. To identify differentially expressed lncRNAs (DELs) between two hypoxia score groups, this study carried out differential expression analysis, and then further integrated with the DELs between controls and CRC patients to generate the hypoxia-related lncRNAs for CRC. Besides, prognostic lncRNAs were screened by the univariate Cox regression, which were later utilized for constructing the prognosis nomogram for CRC by adopting the least absolute shrinkage and selection operator (LASSO) algorithm. In addition, both accuracy and specificity of the constructed prognostic signature were detected through the receiver operating characteristic (ROC) analysis. Moreover, our constructed prognosis signature also was validated in the internal testing test. This study operated gene set enrichment analysis (GSEA) for exploring potential biological functions associated with the prognostic signature. Finally, the ceRNA network of the prognostic lncRNAs was constructed.Results: Among 2299 hypoxia-related lncRNAs of CRC in total, LINC00327, LINC00163, LINC00174, SYNPR-AS1, and MIR31HG were identified as prognostic lncRNAs by the univariate Cox regression, and adopted for constructing the prognosis signature for CRC. ROC analysis showed the predictive power and accuracy of the prognostic signature. Additionally, the GSEA revealed that ECM-receptor interaction, PI3K-Akt pathway, phagosome, and Hippo pathway were mostly associated with the high-risk group. 352 miRNAs-mRNAs pairs and 177 lncRNAs-miRNAs were predicted.Conclusion: To conclude , we identified 5 hypoxia-related lncRNAs to establish an accurate prognostic signature for CRC, providing important prognostic markers and therapeutic target.

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