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The cuproptosis-associated 13 gene signature as a robust predictor for outcome and response to immune- and targeted-therapies in clear cell renal cell carcinoma

Cuproptosis, the newly identified form of regulatory cell death (RCD), results from mitochondrial proteotoxic stress mediated by copper and FDX1. Little is known about significances of cuproptosis in oncogenesis. Here we determined clinical implications of cuproptosis in clear cell renal cell carcin...

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Autores principales: Yuan, Huiyang, Qin, Xin, Wang, Jing, Yang, Qingya, Fan, Yidong, Xu, Dawei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9483097/
https://www.ncbi.nlm.nih.gov/pubmed/36131921
http://dx.doi.org/10.3389/fimmu.2022.971142
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author Yuan, Huiyang
Qin, Xin
Wang, Jing
Yang, Qingya
Fan, Yidong
Xu, Dawei
author_facet Yuan, Huiyang
Qin, Xin
Wang, Jing
Yang, Qingya
Fan, Yidong
Xu, Dawei
author_sort Yuan, Huiyang
collection PubMed
description Cuproptosis, the newly identified form of regulatory cell death (RCD), results from mitochondrial proteotoxic stress mediated by copper and FDX1. Little is known about significances of cuproptosis in oncogenesis. Here we determined clinical implications of cuproptosis in clear cell renal cell carcinoma (ccRCC). Based on the correlation and survival analyses of cuproptosis-correlated genes in TCGA ccRCC cohort, we constructed a cuproptosis-associated 13 gene signature (CuAGS-13) score system. In both TCGA training and two validation cohorts, when patients were categorized into high- and low-risk groups according to a median score as the cutoff, the CuAGS-13 high-risk group was significantly associated with shorter overall survival (OS) and/or progression-free survival (PFS) independently (P<0.001 for all). The CuAGS-13 score assessment could also predict recurrence and recurrence-free survival of patients at stage I – III with a high accuracy, which outperformed the ccAccB/ClearCode34 model, a well-established molecular predictor for ccRCC prognosis. Moreover, patients treated with immune checkpoint inhibitors (ICIs) acquired complete/partial remissions up to 3-time higher coupled with significantly longer PFS in the CuAGS-13 low- than high-risk groups in both training and validation cohorts of ccRCCs (7.2 – 14.1 vs. 2.1 – 3.0 months, P<0.001). The combination of ICI with anti-angiogenic agent Bevacizumab doubled remission rates in CuAGS-13 high-risk patients while did not improve the efficacy in the low-risk group. Further analyses showed a positive correlation between CuAGS-13 and TIDE scores. We also observed that the CuAGS-13 score assessment accurately predicted patient response to Sunitinib, and higher remission rates in the low-risk group led to longer PFS (Low- vs. high-risk, 13.9 vs. 5.8 months, P = 5.0e-12). Taken together, the CuAGS-13 score assessment serves as a robust predictor for survival, recurrence, and response to ICIs, ICI plus anti-angiogenic drugs and Sunitinib in ccRCC patients, which significantly improves patient stratifications for precision medicine of ccRCC.
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spelling pubmed-94830972022-09-20 The cuproptosis-associated 13 gene signature as a robust predictor for outcome and response to immune- and targeted-therapies in clear cell renal cell carcinoma Yuan, Huiyang Qin, Xin Wang, Jing Yang, Qingya Fan, Yidong Xu, Dawei Front Immunol Immunology Cuproptosis, the newly identified form of regulatory cell death (RCD), results from mitochondrial proteotoxic stress mediated by copper and FDX1. Little is known about significances of cuproptosis in oncogenesis. Here we determined clinical implications of cuproptosis in clear cell renal cell carcinoma (ccRCC). Based on the correlation and survival analyses of cuproptosis-correlated genes in TCGA ccRCC cohort, we constructed a cuproptosis-associated 13 gene signature (CuAGS-13) score system. In both TCGA training and two validation cohorts, when patients were categorized into high- and low-risk groups according to a median score as the cutoff, the CuAGS-13 high-risk group was significantly associated with shorter overall survival (OS) and/or progression-free survival (PFS) independently (P<0.001 for all). The CuAGS-13 score assessment could also predict recurrence and recurrence-free survival of patients at stage I – III with a high accuracy, which outperformed the ccAccB/ClearCode34 model, a well-established molecular predictor for ccRCC prognosis. Moreover, patients treated with immune checkpoint inhibitors (ICIs) acquired complete/partial remissions up to 3-time higher coupled with significantly longer PFS in the CuAGS-13 low- than high-risk groups in both training and validation cohorts of ccRCCs (7.2 – 14.1 vs. 2.1 – 3.0 months, P<0.001). The combination of ICI with anti-angiogenic agent Bevacizumab doubled remission rates in CuAGS-13 high-risk patients while did not improve the efficacy in the low-risk group. Further analyses showed a positive correlation between CuAGS-13 and TIDE scores. We also observed that the CuAGS-13 score assessment accurately predicted patient response to Sunitinib, and higher remission rates in the low-risk group led to longer PFS (Low- vs. high-risk, 13.9 vs. 5.8 months, P = 5.0e-12). Taken together, the CuAGS-13 score assessment serves as a robust predictor for survival, recurrence, and response to ICIs, ICI plus anti-angiogenic drugs and Sunitinib in ccRCC patients, which significantly improves patient stratifications for precision medicine of ccRCC. Frontiers Media S.A. 2022-09-05 /pmc/articles/PMC9483097/ /pubmed/36131921 http://dx.doi.org/10.3389/fimmu.2022.971142 Text en Copyright © 2022 Yuan, Qin, Wang, Yang, Fan and Xu 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 Immunology
Yuan, Huiyang
Qin, Xin
Wang, Jing
Yang, Qingya
Fan, Yidong
Xu, Dawei
The cuproptosis-associated 13 gene signature as a robust predictor for outcome and response to immune- and targeted-therapies in clear cell renal cell carcinoma
title The cuproptosis-associated 13 gene signature as a robust predictor for outcome and response to immune- and targeted-therapies in clear cell renal cell carcinoma
title_full The cuproptosis-associated 13 gene signature as a robust predictor for outcome and response to immune- and targeted-therapies in clear cell renal cell carcinoma
title_fullStr The cuproptosis-associated 13 gene signature as a robust predictor for outcome and response to immune- and targeted-therapies in clear cell renal cell carcinoma
title_full_unstemmed The cuproptosis-associated 13 gene signature as a robust predictor for outcome and response to immune- and targeted-therapies in clear cell renal cell carcinoma
title_short The cuproptosis-associated 13 gene signature as a robust predictor for outcome and response to immune- and targeted-therapies in clear cell renal cell carcinoma
title_sort cuproptosis-associated 13 gene signature as a robust predictor for outcome and response to immune- and targeted-therapies in clear cell renal cell carcinoma
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9483097/
https://www.ncbi.nlm.nih.gov/pubmed/36131921
http://dx.doi.org/10.3389/fimmu.2022.971142
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