AUTHOR=Bao Jia-hao , Lu Wei-cheng , Duan Hao , Ye Ya-qi , Li Jiang-bo , Liao Wen-ting , Li Yong-chun , Sun Yang-peng 

TITLE=Identification of a novel cuproptosis-related gene signature and integrative analyses in patients with lower-grade gliomas

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.933973

DOI=10.3389/fimmu.2022.933973

ISSN=1664-3224

ABSTRACT=Background: Cuproptosis is a newly discovered unique non-apoptotic programmed cell death distinguished from known death mechanisms like ferroptosis, pyroptosis, and necroptosis. However, the prognostic value of cuproptosis and the correlation between cuproptosis and tumor microenvironment (TME) in Lower-grade gliomas (LGG) remain unknown. 
Methods: In this study, we systematically investigated genetic and transcriptional variation, prognostic value, and expression patterns of cuproptosis-related genes (CRGs). The CRG score was applied to quantify the cuproptosis subtypes. We then evaluated their values in TME, prognostic prediction, and therapeutic responses in LGG. Lastly, we collected 5 paired LGG and matched normal adjacent tissue samples from Sun Yat-sen University Cancer Center (SYSUCC) to verify the expression of signature genes by quantitative real-time PCR (qRT-PCR) and western blotting (WB).
Results: Two distinct cuproptosis-related clusters were identified using consensus unsupervised clustering analysis. The correlation between multi-layer CRGs alterations with clinical characteristics, prognosis and TME cell infiltration were observed. Then, a well-performed cuproptosis-related risk model (CRG score) was developed to predict LGG patients' prognosis, which was evaluated and validated in two external cohorts. We classified patients into high- and low-risk groups according to the CRG score and found that patients in the low-risk group showed significantly higher survival possibilities than those in the high-risk group (P<0.001). A high CRG score implies higher TME scores, more significant TME cell infiltration and increased mutation burden. Meanwhile, CRG score was significantly correlated with cancer stem cell index, chemoradiotherapy sensitivity-related genes and immune checkpoint genes, and chemotherapeutic sensitivity, indicating the association with CRGs and treatment responses. Univariate and multivariate Cox regression analysis revealed that CRG score was an independent prognostic predictor for LGG patients. Subsequently, a highly accurate predictive model was established for facilitating the clinical application of the CRG score, showing good predictive ability and calibration. Additionally, crucial CRGs were further validated by qRT-PCR and WB.
Conclusion: Collectively, we demonstrated a comprehensive overview of CRG profiles in LGG and established a novel risk model for LGG patients' therapy status and prognosis. Our findings highlight the potential clinical implications of CRGs, suggesting that cuproptosis may be the potential therapeutic target for patients with LGG.