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Development and Validation of a Hypoxia-Related Signature for Predicting Survival Outcomes in Patients With Bladder Cancer
OBJECTIVES: This study aimed to develop and validate a hypoxia signature for predicting survival outcomes in patients with bladder cancer. METHODS: We downloaded the RNA sequence and the clinicopathologic data of the patients with bladder cancer from The Cancer Genome Atlas (TCGA) (https://portal.gd...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188560/ https://www.ncbi.nlm.nih.gov/pubmed/34122523 http://dx.doi.org/10.3389/fgene.2021.670384 |
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author | Zhang, Facai Wang, Xiaoming Bai, Yunjin Hu, Huan Yang, Yubo Wang, Jiahao Tang, Yin Ma, Honggui Feng, Dechao Li, Dengxiong Han, Ping |
author_facet | Zhang, Facai Wang, Xiaoming Bai, Yunjin Hu, Huan Yang, Yubo Wang, Jiahao Tang, Yin Ma, Honggui Feng, Dechao Li, Dengxiong Han, Ping |
author_sort | Zhang, Facai |
collection | PubMed |
description | OBJECTIVES: This study aimed to develop and validate a hypoxia signature for predicting survival outcomes in patients with bladder cancer. METHODS: We downloaded the RNA sequence and the clinicopathologic data of the patients with bladder cancer from The Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov/repository?facetTab=files) and the Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) databases. Hypoxia genes were retrieved from the Molecular Signatures Database (https://www.gsea-msigdb.org/gsea/msigdb/index.jsp). Differentially expressed hypoxia-related genes were screened by univariate Cox regression analysis and Lasso regression analysis. Then, the selected genes constituted the hypoxia signature and were included in multivariate Cox regression to generate the risk scores. After that, we evaluate the predictive performance of this signature by multiple receiver operating characteristic (ROC) curves. The CIBERSORT tool was applied to investigate the relationship between the hypoxia signature and the immune cell infiltration, and the maftool was used to summarize and analyze the mutational data. Gene-set enrichment analysis (GSEA) was used to investigate the related signaling pathways of differentially expressed genes in both risk groups. Furthermore, we developed a model and presented it with a nomogram to predict survival outcomes in patients with bladder cancer. RESULTS: Eight genes (AKAP12, ALDOB, CASP6, DTNA, HS3ST1, JUN, KDELR3, and STC1) were included in the hypoxia signature. The patients with higher risk scores showed worse overall survival time than the ones with lower risk scores in the training set (TCGA) and two external validation sets (GSE13507 and GSE32548). Immune infiltration analysis showed that two types of immune cells (M0 and M1 macrophages) had a significant infiltration in the high-risk group. Tumor mutation burden (TMB) analysis showed that the risk scores between the wild types and the mutation types of TP53, MUC16, RB1, and FGFR3 were significantly different. Gene-Set Enrichment Analysis (GSEA) showed that immune or cancer-associated pathways belonged to the high-risk groups and metabolism-related signal pathways were enriched into the low-risk group. Finally, we constructed a predictive model with risk score, age, and stage and validated its performance in GEO datasets. CONCLUSION: We successfully constructed and validated a novel hypoxia signature in bladder cancer, which could accurately predict patients’ prognosis. |
format | Online Article Text |
id | pubmed-8188560 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-81885602021-06-10 Development and Validation of a Hypoxia-Related Signature for Predicting Survival Outcomes in Patients With Bladder Cancer Zhang, Facai Wang, Xiaoming Bai, Yunjin Hu, Huan Yang, Yubo Wang, Jiahao Tang, Yin Ma, Honggui Feng, Dechao Li, Dengxiong Han, Ping Front Genet Genetics OBJECTIVES: This study aimed to develop and validate a hypoxia signature for predicting survival outcomes in patients with bladder cancer. METHODS: We downloaded the RNA sequence and the clinicopathologic data of the patients with bladder cancer from The Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov/repository?facetTab=files) and the Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) databases. Hypoxia genes were retrieved from the Molecular Signatures Database (https://www.gsea-msigdb.org/gsea/msigdb/index.jsp). Differentially expressed hypoxia-related genes were screened by univariate Cox regression analysis and Lasso regression analysis. Then, the selected genes constituted the hypoxia signature and were included in multivariate Cox regression to generate the risk scores. After that, we evaluate the predictive performance of this signature by multiple receiver operating characteristic (ROC) curves. The CIBERSORT tool was applied to investigate the relationship between the hypoxia signature and the immune cell infiltration, and the maftool was used to summarize and analyze the mutational data. Gene-set enrichment analysis (GSEA) was used to investigate the related signaling pathways of differentially expressed genes in both risk groups. Furthermore, we developed a model and presented it with a nomogram to predict survival outcomes in patients with bladder cancer. RESULTS: Eight genes (AKAP12, ALDOB, CASP6, DTNA, HS3ST1, JUN, KDELR3, and STC1) were included in the hypoxia signature. The patients with higher risk scores showed worse overall survival time than the ones with lower risk scores in the training set (TCGA) and two external validation sets (GSE13507 and GSE32548). Immune infiltration analysis showed that two types of immune cells (M0 and M1 macrophages) had a significant infiltration in the high-risk group. Tumor mutation burden (TMB) analysis showed that the risk scores between the wild types and the mutation types of TP53, MUC16, RB1, and FGFR3 were significantly different. Gene-Set Enrichment Analysis (GSEA) showed that immune or cancer-associated pathways belonged to the high-risk groups and metabolism-related signal pathways were enriched into the low-risk group. Finally, we constructed a predictive model with risk score, age, and stage and validated its performance in GEO datasets. CONCLUSION: We successfully constructed and validated a novel hypoxia signature in bladder cancer, which could accurately predict patients’ prognosis. Frontiers Media S.A. 2021-05-26 /pmc/articles/PMC8188560/ /pubmed/34122523 http://dx.doi.org/10.3389/fgene.2021.670384 Text en Copyright © 2021 Zhang, Wang, Bai, Hu, Yang, Wang, Tang, Ma, Feng, Li and Han. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Genetics Zhang, Facai Wang, Xiaoming Bai, Yunjin Hu, Huan Yang, Yubo Wang, Jiahao Tang, Yin Ma, Honggui Feng, Dechao Li, Dengxiong Han, Ping Development and Validation of a Hypoxia-Related Signature for Predicting Survival Outcomes in Patients With Bladder Cancer |
title | Development and Validation of a Hypoxia-Related Signature for Predicting Survival Outcomes in Patients With Bladder Cancer |
title_full | Development and Validation of a Hypoxia-Related Signature for Predicting Survival Outcomes in Patients With Bladder Cancer |
title_fullStr | Development and Validation of a Hypoxia-Related Signature for Predicting Survival Outcomes in Patients With Bladder Cancer |
title_full_unstemmed | Development and Validation of a Hypoxia-Related Signature for Predicting Survival Outcomes in Patients With Bladder Cancer |
title_short | Development and Validation of a Hypoxia-Related Signature for Predicting Survival Outcomes in Patients With Bladder Cancer |
title_sort | development and validation of a hypoxia-related signature for predicting survival outcomes in patients with bladder cancer |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188560/ https://www.ncbi.nlm.nih.gov/pubmed/34122523 http://dx.doi.org/10.3389/fgene.2021.670384 |
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