Dataset Information

Construction and validation of a novel Ferroptosis-related gene signature predictive model in rectal Cancer.

ABSTRACT:

Background

Rectal cancer (RC) is one of the most common malignant tumors. Ferroptosis is an iron-dependent form of cell death, which plays an important role in various cancers. However, the correlation between ferroptosis-related genes (FRGs) and prognosis in RC remains unclear.

Methods

Gene expression data from The Cancer Genome Atlas Rectum adenocarcinoma (TCGA-READ) and GSE87211 were downloaded. Clustering and functional enrichment were evaluated. A FRGs risk score was established based on the univariate Cox analysis and the Least absolute shrinkage and selection operator (LASSO) analysis. K-M analysis and ROC analysis were conducted to determine prognostic values. qRT-PCR was performed to validate levels of mRNA expression. Multivariate Cox analysis was used to build a prognostic prediction model based on the risk score.

Results

Based on FRGs, RC patients were grouped into two clusters. In the functional enrichment of differentially expressed genes between the two clusters, immune-related pathways dominated. A novel FRGs signature with 14 genes related to the overall survival (OS) of RC was established. qRT-PCR of the 14 genes identified TP63, ISCU, PLIN4, MAP3K5, OXSR, FANCD2 and ATM were overexpressed in RC tissue; HSPB1, MAPK1, ABCC1, PANX1, MAPK9 and ATG7 were underexpressed; TUBE1 had no difference. The high-risk group had a significantly lower OS than the low-risk group (P < 0.001), and ROC curve analysis confirmed the signature's predictive capacity. Multivariate analysis demonstrated that the risk score and age were independent prognostic factors.

Conclusion

A novel FRGs model can be used to predict the prognosis in RC, as well as to guide individual treatment.

SUBMITTER: Shi WK

PROVIDER: S-EPMC9682793 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Publications

Construction and validation of a novel Ferroptosis-related gene signature predictive model in rectal Cancer.

Shi Wei-Kun WK Liu Yu-Xin YX Qiu Xiao-Yuan XY Zhou Jing-Ya JY Zhou Jiao-Lin JL Lin Guo-Le GL

BMC genomics 20221122 1

<h4>Background</h4>Rectal cancer (RC) is one of the most common malignant tumors. Ferroptosis is an iron-dependent form of cell death, which plays an important role in various cancers. However, the correlation between ferroptosis-related genes (FRGs) and prognosis in RC remains unclear.<h4>Methods</h4>Gene expression data from The Cancer Genome Atlas Rectum adenocarcinoma (TCGA-READ) and GSE87211 were downloaded. Clustering and functional enrichment were evaluated. A FRGs risk score was establis ...[more]

PMID: 36414988

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Project description:BackgroundLung cancer has the highest prevalence and mortality of all cancers, and lung adenocarcinoma (LUAD) occupies the largest proportion of lung cancers. Herein, this study is aimed at constructing a ferroptosis-related prognostic signature for LUAD and conducting functional analysis based on the signature, highlighting the importance of ferroptosis in LUAD.MethodsWe employed RNA-sequencing (RNA-seq) and clinical data from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression, Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis were conducted to build the ferroptosis-related genes (FRGs) prognostic signature. The efficacy of this FRG signature was further analyzed with Kaplan-Meier (KM) plot, multivariate Cox regression, and the receiver operating characteristic (ROC) curves. Enrichment analysis was used to evaluate key pathways. The expression of immunomodulators, immune infiltration status, and drug sensitivity correlation were explored to predict the response to various therapies. The expression of FRGs was validated in LUAD samples with western blot (WB) and immunohistochemistry (IHC) staining. Cell viability assay and lipid peroxidation detection were measured after small interfering RNA (siRNA) knockdown of two FRGs in lung cancer cell lines.ResultsA seven-gene signature was constructed and used to divide LUAD patients into high- and low-risk groups. High-risk patients were notably related to shorter overall survival (OS), and multivariate Cox regression demonstrated that our signature was an independent predictor of OS. ROC curve analysis presented a maximum area under the curve (AUC) value of 0.740 for the experimental cohort and 0.705 for the validation cohort. The low-risk group showed higher levels of plasma cell infiltration and higher expression of programmed cell death protein 1 (PDCD1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Ferroptosis inducers such as talazoparib or cisplatin had lower IC50 values in the high-risk group, while navitoclax (BCL-2 gene family inhibition and apoptosis inducer) had higher IC50 values in the high-risk group. Additionally, peroxiredoxin-6 (PRDX6) and acyl-CoA synthetase long chain family member 3 (ACSL3) were upregulated in LUAD tissues. Lipid peroxide assay showed that silencing PRDX6 or ACSL3 promoted lipid peroxidation and ferroptosis in lung cancer cells.ConclusionsOur novel ferroptosis-related signature shows potential clinical and functional importance in LUAD patients, and further research on ferroptosis as a therapeutic target in LUAD is warranted.

Project description:Purpose: To identify whether ferroptosis-related genes play predictive roles in bladder cancer patients and to develop a ferroptosis-related gene signature to predict overall survival outcomes. Materials and Methods: We downloaded the mRNA expression files and clinical data of 256 bladder samples (188 bladder tumour and 68 nontumour samples) from the GEO database and 430 bladder samples (411 bladder tumour and 19 nontumour samples) from the TCGA database. A multigene signature based on prognostic ferroptosis-related genes was constructed by least absolute shrinkage and selection operator Cox regression analysis in the GEO cohort. The TCGA cohort was used to validate the ferroptosis-related gene signature. Next, functional enrichment analysis, including both Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses, was performed to elucidate the mechanism underlying the signature. The ssGSEA scores of 16 immune cells and 13 immune-related pathway activities between the high-risk and low-risk groups were also analysed in our study. Results: Thirty-three (67.3%) ferroptosis-related genes were differentially expressed between bladder tumour samples and nontumour samples in the GEO cohort. The intersection of prognostic ferroptosis-related genes and differentially expressed genes identified four prognostic targets, including ALOX5, FANCD2, HMGCR and FADS2. The least absolute shrinkage and selection operator Cox regression successfully built a 4-gene signature: risk score value = esum (each gene's normalized expression * each gene's coefficient). Univariate and multivariate Cox regression analyses were performed in both the GEO and TCGA cohorts to test the independent prognostic value of the 4-gene risk signature. Multivariate Cox regression analysis in the GEO cohort identified age (p < 0.001), grade (p = 0.129) and risk score (p = 0.016) as independent prognostic predictors for overall survival. Multivariate Cox regression analysis in the TCGA cohort also identified age (p = 0.002), stage (p < 0.001) and risk score (p = 0.006) as independent prognostic predictors for overall survival. The type II IFN response was determined to be significantly weakened in the high-risk group in both the GEO and TCGA cohorts. Conclusion: We successfully built a ferroptosis-related gene signature of significant predictive value for bladder cancer. These results suggest a novel research direction for targeted therapy of bladder cancer in the future.

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Dataset Information

Construction and validation of a novel Ferroptosis-related gene signature predictive model in rectal Cancer.

Background

Methods

Results

Conclusion

Publications

Construction and validation of a novel Ferroptosis-related gene signature predictive model in rectal Cancer.

Similar Datasets

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