Identification of a prognostic model using cuproptosis-related genes in uveal melanoma

Abstract

The most common intraocular malignancy in adults remains uveal melanoma (UVM), and those with metastatic disease have a poor outlook. Proliferation, angiogenesis, and metastasis of tumor cells can be triggered by cuproptosis, affecting the survival of cancer patients. Nonetheless, cuproptosis-related genes (CRGs) have not been identified in UVM. In this study, we analyzed 10 CRGs in 80 patients with UVM in the Cancer Genome Atlas (TCGA) database regarding the alterations of the genes including copy number variation and methylation. We further constructed a prognostic gene model using these CRGs and built the risk score formula. Univariate and multivariate Cox regression was applied to validate the risk score as an independent prognostic factor. The prognostic model was validated using 63 UVM samples from the GSE22138 cohort, an independent validation data set. Based on the risk scores for 80 patients with UVM from TCGA, we categorized the patients into high- and low-risk groups. Differentially expressed genes (DEGs) between groups were enriched in allograft rejection, hypoxia, glycolysis, TNFα signaling via NF-κB, and interferon-γ responses via Gene set enrichment analysis (GSEA). CD8 T cells and exhausted T cells were notably enriched in the high-risk group. In conclusion, the alteration of CRGs is related to patients with UVM, and the constructed CRG-related model may be helpful to predict the prognosis of such patients.

Cuproptosis: mechanisms and links with cancers

“…CKGs have different roles among different tumors. DLD was considered as a risk factor in studies of different tumors such as uveal melanoma(UVM), glioma, and LUAD [ 129 , 139 , 143 , 183 ]. In contrast, LIAS was analyzed as a protective factor in studies of UVM, glioma, and pancreatic adenocarcinoma(PAAD) [ 139 , 142 , 156 – 158 ].…”

“…DLD was considered as a risk factor in studies of different tumors such as uveal melanoma(UVM), glioma, and LUAD [ 129 , 139 , 143 , 183 ]. In contrast, LIAS was analyzed as a protective factor in studies of UVM, glioma, and pancreatic adenocarcinoma(PAAD) [ 139 , 142 , 156 – 158 ]. In studies, DLAT was analyzed as a PAAD risk factor [ 156 – 158 ] and conversely was considered to be associated with a protective effect in glioma [ 142 , 143 ].…”

“…Even in different studies on the same tumor, different investigators considered FDX1 and PDHA1 as risk or protective factor respectively [ 129 , 130 , 148 , 149 ]. A potential association among CDKN2A, MTF1 and GLS and patient prognosis has been noted in different studies, which were believed had a consistent effect on the prognosis of patients [ 130 , 131 , 139 , 156 ]. In one of the researches on glioma, SLC31A1 was considered a risk factor, while ATP7B was considered a protective factor [ 142 ], which further suggested that there may be a link between the copper homeostasis and cancer.…”

“…In most studies validated using immunotherapy cohorts, the low-risk group had a better prognosis for immunotherapy [ 152 , 156 , 158 , 173 , 194 ], except for those on glioma [ 140 , 141 ]. Moreover, in the study on UVM, it has been found that immunotherapy was ineffective in both populations [ 139 ]. Due to the lack of biological evidence, it remains unclear what role these cuproptosis-related genes might play in the immunotherapeutic process of patients.…”

Role of a cuproptosis-related prognostic signature in uveal melanoma tumor microenvironment and immune responses

“…Copper-dependent and copper-regulated cell death differ from established death mechanisms by relying on mitochondrial respiration via direct copper binding to the lipidated components of the tricarboxylic acid cycle, resulting in lipidated protein aggregation and subsequent loss of iron-sulfur cluster proteins, causing proteotoxic stress and ultimately cell death (Tang et al, 2022). Considering the potential of a novel copper-related cell death mechanism in cancer progression, namely, cuproptosis, a research of UVM initially investigated the relationship between cuproptosis and UVM progress through a series of bioinformatics algorithms based on ten cuproptosis-related genes (CRGs), and con rmed the prognostic utilize of cuproptosis-related genes in UVM for the rst time (Chen et al, 2022b). While, few studies targeting the combination of bulksequencing and single-cell RNA sequencing (scRNA-seq) data on cuproptosis related genes (CRGs) in UVM have been reported.…”