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Construction and Validation of a Novel Immunosignature for Overall Survival in Uveal Melanoma

OBJECTIVES: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, and immune infiltration plays a crucial role in the prognosis of UM. This study aimed to generate an immunological marker-based predictive signature for the overall survival (OS) of UM patients. METHODS: Sin...

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Autores principales: Gu, Chufeng, Gu, Xin, Wang, Yujie, Yao, Zhixian, Zhou, Chuandi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450517/
https://www.ncbi.nlm.nih.gov/pubmed/34552928
http://dx.doi.org/10.3389/fcell.2021.710558
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author Gu, Chufeng
Gu, Xin
Wang, Yujie
Yao, Zhixian
Zhou, Chuandi
author_facet Gu, Chufeng
Gu, Xin
Wang, Yujie
Yao, Zhixian
Zhou, Chuandi
author_sort Gu, Chufeng
collection PubMed
description OBJECTIVES: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, and immune infiltration plays a crucial role in the prognosis of UM. This study aimed to generate an immunological marker-based predictive signature for the overall survival (OS) of UM patients. METHODS: Single-sample gene-set enrichment analysis (ssGSEA) was used to profile immune cell infiltration in 79 patients with UM from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate least absolute shrinkage and selection operator (LASSO) Cox regressions were used to determine the prognostic factors for UM and construct the predictive immunosignature. Receiver operating characteristic (ROC) curves, decision curve analysis (DCA), and calibration curves were performed to evaluate the clinical ability and accuracy of the model. In addition, the predictive accuracy was compared between the immunosignature and the Tumor, Node, Metastasis (TNM) staging system of American Joint Committee on Cancer (AJCC). We further analyzed the differences in clinical characteristics, immune infiltrates, immune checkpoints, and therapy sensitivity between high- and low-risk groups characterized by the prognostic model. RESULTS: Higher levels of immune cell infiltration in UM were related to a lower survival rate. Matrix metallopeptidase 12 (MMP12), TCDD inducible poly (ADP-ribose) polymerase (TIPARP), and leucine rich repeat neuronal 3 (LRRN3) were identified as prognostic signatures, and an immunological marker-based prognostic signature was constructed with good clinical ability and accuracy. The immunosignature was developed with a concordance index (C-index) of 0.881, which is significantly better than that of the TNM staging system (p < 0.001). We further identified 1,762 genes with upregulated expression and 798 genes with downregulated expression in the high-risk group, and the differences between the high- and low-risk groups were mainly in immune-related processes. In addition, the expression of most of the immune checkpoint-relevant and immune activity-relevant genes was significantly higher in the high-risk group, which was more sensitive to therapy. CONCLUSION: We developed a novel immunosignature constructed by MMP12, TIPARP, and LRRN3 that could effectively predict the OS of UM.
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spelling pubmed-84505172021-09-21 Construction and Validation of a Novel Immunosignature for Overall Survival in Uveal Melanoma Gu, Chufeng Gu, Xin Wang, Yujie Yao, Zhixian Zhou, Chuandi Front Cell Dev Biol Cell and Developmental Biology OBJECTIVES: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, and immune infiltration plays a crucial role in the prognosis of UM. This study aimed to generate an immunological marker-based predictive signature for the overall survival (OS) of UM patients. METHODS: Single-sample gene-set enrichment analysis (ssGSEA) was used to profile immune cell infiltration in 79 patients with UM from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate least absolute shrinkage and selection operator (LASSO) Cox regressions were used to determine the prognostic factors for UM and construct the predictive immunosignature. Receiver operating characteristic (ROC) curves, decision curve analysis (DCA), and calibration curves were performed to evaluate the clinical ability and accuracy of the model. In addition, the predictive accuracy was compared between the immunosignature and the Tumor, Node, Metastasis (TNM) staging system of American Joint Committee on Cancer (AJCC). We further analyzed the differences in clinical characteristics, immune infiltrates, immune checkpoints, and therapy sensitivity between high- and low-risk groups characterized by the prognostic model. RESULTS: Higher levels of immune cell infiltration in UM were related to a lower survival rate. Matrix metallopeptidase 12 (MMP12), TCDD inducible poly (ADP-ribose) polymerase (TIPARP), and leucine rich repeat neuronal 3 (LRRN3) were identified as prognostic signatures, and an immunological marker-based prognostic signature was constructed with good clinical ability and accuracy. The immunosignature was developed with a concordance index (C-index) of 0.881, which is significantly better than that of the TNM staging system (p < 0.001). We further identified 1,762 genes with upregulated expression and 798 genes with downregulated expression in the high-risk group, and the differences between the high- and low-risk groups were mainly in immune-related processes. In addition, the expression of most of the immune checkpoint-relevant and immune activity-relevant genes was significantly higher in the high-risk group, which was more sensitive to therapy. CONCLUSION: We developed a novel immunosignature constructed by MMP12, TIPARP, and LRRN3 that could effectively predict the OS of UM. Frontiers Media S.A. 2021-09-06 /pmc/articles/PMC8450517/ /pubmed/34552928 http://dx.doi.org/10.3389/fcell.2021.710558 Text en Copyright © 2021 Gu, Gu, Wang, Yao and Zhou. 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
Gu, Chufeng
Gu, Xin
Wang, Yujie
Yao, Zhixian
Zhou, Chuandi
Construction and Validation of a Novel Immunosignature for Overall Survival in Uveal Melanoma
title Construction and Validation of a Novel Immunosignature for Overall Survival in Uveal Melanoma
title_full Construction and Validation of a Novel Immunosignature for Overall Survival in Uveal Melanoma
title_fullStr Construction and Validation of a Novel Immunosignature for Overall Survival in Uveal Melanoma
title_full_unstemmed Construction and Validation of a Novel Immunosignature for Overall Survival in Uveal Melanoma
title_short Construction and Validation of a Novel Immunosignature for Overall Survival in Uveal Melanoma
title_sort construction and validation of a novel immunosignature for overall survival in uveal melanoma
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450517/
https://www.ncbi.nlm.nih.gov/pubmed/34552928
http://dx.doi.org/10.3389/fcell.2021.710558
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