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A Ferroptosis-Related Gene Prognostic Index to Predict Temozolomide Sensitivity and Immune Checkpoint Inhibitor Response for Glioma
Background: Gliomas are highly lethal brain tumors. Despite multimodality therapy with surgery, radiotherapy, chemotherapy, and immunotherapy, glioma prognosis remains poor. Ferroptosis is a crucial tumor suppressor mechanism that has been proven to be effective in anticancer therapy. However, the i...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8842730/ https://www.ncbi.nlm.nih.gov/pubmed/35174170 http://dx.doi.org/10.3389/fcell.2021.812422 |
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author | Cai, Yonghua Liang, Xianqiu Zhan, Zhengming Zeng, Yu Lin, Jie Xu, Anqi Xue, Shuaishuai Xu, Wei Chai, Peng Mao, Yangqi Song, Zibin Han, Lei Xiao, Jianqi Song, Ye Zhang, Xian |
author_facet | Cai, Yonghua Liang, Xianqiu Zhan, Zhengming Zeng, Yu Lin, Jie Xu, Anqi Xue, Shuaishuai Xu, Wei Chai, Peng Mao, Yangqi Song, Zibin Han, Lei Xiao, Jianqi Song, Ye Zhang, Xian |
author_sort | Cai, Yonghua |
collection | PubMed |
description | Background: Gliomas are highly lethal brain tumors. Despite multimodality therapy with surgery, radiotherapy, chemotherapy, and immunotherapy, glioma prognosis remains poor. Ferroptosis is a crucial tumor suppressor mechanism that has been proven to be effective in anticancer therapy. However, the implications of ferroptosis on the clinical prognosis, chemotherapy, and immune checkpoint inhibitor (ICI) therapy for patients with glioma still need elucidation. Methods: Consensus clustering revealed two distinct ferroptosis-related subtypes based on the Cancer Genome Atlas (TCGA) glioma dataset (n = 663). Subsequently, the ferroptosis-related gene prognostic index (FRGPI) was constructed by weighted gene co-expression network analysis (WGCNA) and “stepAIC” algorithms and validated with the Chinese Glioma Genome Atlas (CGGA) dataset (n = 404). Subsequently, the correlation among clinical, molecular, and immune features and FRGPI was analyzed. Next, the temozolomide sensitivity and ICI response for glioma were predicted using the “pRRophetic” and “TIDE” algorithms, respectively. Finally, candidate small molecular drugs were defined using the connectivity map database based on FRGPI. Results: The FRGPI was established based on the HMOX1, TFRC, JUN, and SOCS1 genes. The distribution of FRGPI varied significantly among the different ferroptosis-related subtypes. Patients with high FRGPI had a worse overall prognosis than patients with low FRGPI, consistent with the results in the CGGA dataset. The final results showed that high FRGPI was characterized by more aggressive phenotypes, high PD-L1 expression, high tumor mutational burden score, and enhanced temozolomide sensitivity; low FRGPI was associated with less aggressive phenotypes, high microsatellite instability score, and stronger response to immune checkpoint blockade. In addition, the infiltration of memory resting CD4(+) T cells, regulatory T cells, M1 macrophages, M2 macrophages, and neutrophils was positively correlated with FRGPI. In contrast, plasma B cells and naïve CD4(+) T cells were negatively correlated. A total of 15 potential small molecule compounds (such as depactin, physostigmine, and phenacetin) were identified. Conclusion: FRGPI is a promising gene panel for predicting the prognosis, immune characteristics, temozolomide sensitivity, and ICI response in patients with glioma. |
format | Online Article Text |
id | pubmed-8842730 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-88427302022-02-15 A Ferroptosis-Related Gene Prognostic Index to Predict Temozolomide Sensitivity and Immune Checkpoint Inhibitor Response for Glioma Cai, Yonghua Liang, Xianqiu Zhan, Zhengming Zeng, Yu Lin, Jie Xu, Anqi Xue, Shuaishuai Xu, Wei Chai, Peng Mao, Yangqi Song, Zibin Han, Lei Xiao, Jianqi Song, Ye Zhang, Xian Front Cell Dev Biol Cell and Developmental Biology Background: Gliomas are highly lethal brain tumors. Despite multimodality therapy with surgery, radiotherapy, chemotherapy, and immunotherapy, glioma prognosis remains poor. Ferroptosis is a crucial tumor suppressor mechanism that has been proven to be effective in anticancer therapy. However, the implications of ferroptosis on the clinical prognosis, chemotherapy, and immune checkpoint inhibitor (ICI) therapy for patients with glioma still need elucidation. Methods: Consensus clustering revealed two distinct ferroptosis-related subtypes based on the Cancer Genome Atlas (TCGA) glioma dataset (n = 663). Subsequently, the ferroptosis-related gene prognostic index (FRGPI) was constructed by weighted gene co-expression network analysis (WGCNA) and “stepAIC” algorithms and validated with the Chinese Glioma Genome Atlas (CGGA) dataset (n = 404). Subsequently, the correlation among clinical, molecular, and immune features and FRGPI was analyzed. Next, the temozolomide sensitivity and ICI response for glioma were predicted using the “pRRophetic” and “TIDE” algorithms, respectively. Finally, candidate small molecular drugs were defined using the connectivity map database based on FRGPI. Results: The FRGPI was established based on the HMOX1, TFRC, JUN, and SOCS1 genes. The distribution of FRGPI varied significantly among the different ferroptosis-related subtypes. Patients with high FRGPI had a worse overall prognosis than patients with low FRGPI, consistent with the results in the CGGA dataset. The final results showed that high FRGPI was characterized by more aggressive phenotypes, high PD-L1 expression, high tumor mutational burden score, and enhanced temozolomide sensitivity; low FRGPI was associated with less aggressive phenotypes, high microsatellite instability score, and stronger response to immune checkpoint blockade. In addition, the infiltration of memory resting CD4(+) T cells, regulatory T cells, M1 macrophages, M2 macrophages, and neutrophils was positively correlated with FRGPI. In contrast, plasma B cells and naïve CD4(+) T cells were negatively correlated. A total of 15 potential small molecule compounds (such as depactin, physostigmine, and phenacetin) were identified. Conclusion: FRGPI is a promising gene panel for predicting the prognosis, immune characteristics, temozolomide sensitivity, and ICI response in patients with glioma. Frontiers Media S.A. 2022-01-31 /pmc/articles/PMC8842730/ /pubmed/35174170 http://dx.doi.org/10.3389/fcell.2021.812422 Text en Copyright © 2022 Cai, Liang, Zhan, Zeng, Lin, Xu, Xue, Xu, Chai, Mao, Song, Han, Xiao, Song and Zhang. 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 | Cell and Developmental Biology Cai, Yonghua Liang, Xianqiu Zhan, Zhengming Zeng, Yu Lin, Jie Xu, Anqi Xue, Shuaishuai Xu, Wei Chai, Peng Mao, Yangqi Song, Zibin Han, Lei Xiao, Jianqi Song, Ye Zhang, Xian A Ferroptosis-Related Gene Prognostic Index to Predict Temozolomide Sensitivity and Immune Checkpoint Inhibitor Response for Glioma |
title | A Ferroptosis-Related Gene Prognostic Index to Predict Temozolomide Sensitivity and Immune Checkpoint Inhibitor Response for Glioma |
title_full | A Ferroptosis-Related Gene Prognostic Index to Predict Temozolomide Sensitivity and Immune Checkpoint Inhibitor Response for Glioma |
title_fullStr | A Ferroptosis-Related Gene Prognostic Index to Predict Temozolomide Sensitivity and Immune Checkpoint Inhibitor Response for Glioma |
title_full_unstemmed | A Ferroptosis-Related Gene Prognostic Index to Predict Temozolomide Sensitivity and Immune Checkpoint Inhibitor Response for Glioma |
title_short | A Ferroptosis-Related Gene Prognostic Index to Predict Temozolomide Sensitivity and Immune Checkpoint Inhibitor Response for Glioma |
title_sort | ferroptosis-related gene prognostic index to predict temozolomide sensitivity and immune checkpoint inhibitor response for glioma |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8842730/ https://www.ncbi.nlm.nih.gov/pubmed/35174170 http://dx.doi.org/10.3389/fcell.2021.812422 |
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