Cuproptosis scoring model predicts overall survival and assists in immunotherapeutic decision making in pancreatic carcinoma

Abstract

Background: Cuproptosis is a newly identified form of non-apoptotic cell death that is associated with the progression and treatment responses in pancreatic adenocarcinoma (PAAD). However, its impact on oncology and tumor microenvironment (TME) remains unclear.Methods: Hub genes were identified using least absolute shrinkage and selection operator (LASSO) Cox regression for 25 newly reported cuproptosis-related regulators and subjected to stepwise regression to obtain cuproptosis-related score (CuRS). Additionally, the clinical significance, functional status, role on TME, and genomic variation of CuRS were further examined systematically.Results: A CuRS model incorporating TRAF2, TRADD, USP21, FAS, MLKL, TNFRSF10B, MAPK8, TRAF5, and RIPK3 was developed. The stability and accuracy of this risk model as an independent prognostic factor for PAAD were confirmed in the training and external validation cohorts. Patients in the high-CuRS group had “cold” tumors with active tumor proliferation and immunosuppression, whereas those in the low-CuRS group comprised “hot” tumors with active immune function and cell killing capacity. Additionally, patients in the high-CuRS group carried fewer genomic copy number variations (CNVs) and greater somatic mutations. Furthermore, patients in the low- and high-CuRS groups exhibited increased sensitivity to immunotherapy and chemotherapy, respectively.Conclusion: We developed and validated a robust CuRS model based on cuproptosis to assess patients’ prognoses and guide clinical decision-making. Overall, the findings of this study are expected to contribute to the comprehensive understanding of cuproptosis and facilitate precise treatment of PAAD.

Cuproptosis: mechanisms and links with cancers

“…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 ].…”

“…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 ].…”

“…However, most of these researchers predict the efficacy indirectly by the expression level of immune checkpoint genes or TIDE scores, only in some studies, investigators used the immunotherapy cohorts from the public databases to directly evaluate the prognosis of patients under immunotherapy. 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 ].…”

Establishment of a 7-gene prognostic signature based on oxidative stress genes for predicting chemotherapy resistance in pancreatic cancer

“…We also assessed model reliability by decision curve analysis, and in comparison to the extreme curves, benefit of both RiskScore and Nomogram was significantly greater and the two showed a stronger survival prediction (Figure 9I). Herein, we selected three risk models from previous studies (5gene signature (Yan) (Yan et al, 2022), 3-gene signature (Yang) (Yang et al, 2022) and 9-gene signature (Liu) (Liu et al, 2022)) to compare with our model. In order to make the model have a certain comparability, the same method is used to calculate the sample risk score according to the corresponding genes in the three models, and zscore is performed for Riskscore.…”

Development and validation of a cuproptosis-associated prognostic model for diffuse large B-cell lymphoma

“…Not surprisingly, the oxidative phosphorylation inhibitor Gboxin analog was found to have a strong proliferation inhibitory and cell cycle blocking effect on DLBCL with specific selectivity for it ( 34 ). Several recent studies have revealed the potential role of CRGs in the prognosis of cancers, such as kidney cancer ( 35 – 42 ), hepatocellular carcinoma ( 43 – 47 ), lung cancer ( 48 – 53 ), head and neck squamous cell carcinoma ( 53 – 60 ), glioma ( 61 – 66 ), breast cancer ( 67 – 70 ), endometrial carcinoma ( 71 , 72 ), melanoma ( 73 – 75 ), pancreatic cancer ( 76 , 77 ), colorectal cancer ( 78 – 81 ) and so on. However, no reports describe any effects of the cuproptosis regulatory mechanism on DLBCL.…”