Ferroptosis-related lncRNA signature predicts prognosis and immunotherapy efficacy in cutaneous melanoma

Abstract

PurposeFerroptosis-related lncRNAs are promising biomarkers for predicting the prognosis of many cancers. However, a ferroptosis-related signature to predict the prognosis of cutaneous melanoma (CM) has not been identified. The purpose of this study was to construct a ferroptosis-related lncRNA signature to predict prognosis and immunotherapy efficacy in CM.MethodsFerroptosis-related differentially expressed genes (FDEGs) and lncRNAs (FDELs) were identified using TCGA, GTEx, and FerrDb datasets. We performed Cox and LASSO regressions to identify key FDELs, and constructed a risk score to stratify patients into high- and low-risk groups. The lncRNA signature was evaluated using the areas under the receiver operating characteristic curves (AUCs) and Kaplan-Meier analyses in the training, testing, and entire cohorts. Multivariate Cox regression analyses including the lncRNA signature and common clinicopathological characteristics were performed to identify independent predictors of overall survival (OS). A nomogram was developed for clinical use. We performed gene set enrichment analyses (GSEA) to identify significantly enriched pathways. Differences in the tumor microenvironment (TME) between the 2 groups were assessed using 7 algorithms. To predict the efficacy of immune checkpoint inhibitors (ICI), we analyzed the association between PD1 and CTLA4 expression and the risk score. Finally, differences in Tumor Mutational Burden (TMB) and molecular drugs Sensitivity between the 2 groups were performed.ResultsWe identified 5 lncRNAs (AATBC, AC145423.2, LINC01871, AC125807.2, and AC245041.1) to construct the risk score. The AUC of the lncRNA signature was 0.743 in the training cohort and was validated in the testing and entire cohorts. Kaplan-Meier analyses revealed that the high-risk group had poorer prognosis. Multivariate Cox regression showed that the lncRNA signature was an independent predictor of OS with higher accuracy than traditional clinicopathological features. The 1-, 3-, and 5-year survival probabilities for CM patients were 92.7%, 57.2%, and 40.2% with an AUC of 0.804, indicating a good accuracy and reliability of the nomogram. GSEA showed that the high-risk group had lower ferroptosis and immune response. TME analyses confirmed that the high-risk group had lower immune cell infiltration (e.g., CD8+ T cells, CD4+ memory-activated T cells, and M1 macrophages) and lower immune functions (e.g., immune checkpoint activation). Low-risk patients whose disease expressed PD1 or CTLA4 were likely to respond better to ICIs. The analysis demonstrated that the TMB had significantly difference between low- and high- risk groups. Chemotherapy drugs, such as sorafenib, Imatinib, ABT.888 (Veliparib), Docetaxel, and Paclitaxel showed Significant differences in the estimated IC50 between the two risk groups.ConclusionOur novel ferroptosis-related lncRNA signature was able to accurately predict the prognosis and ICI outcomes of CM patients. These ferroptosis-related lncRNAs might be potential biomarkers and therapeutic targets for CM.

Long non‐coding RNA as a potential diagnostic and prognostic biomarker in melanoma: A systematic review and meta‐analysis

“…Xu et al. created a novel signature based on five lncRNAs, including AATBC, AC145423.2, LINC01871, AC125807.2 and AC245041.1, that can predict the clinical outcome in melanoma patients 34 . Also, Ma et al.…”

“…Also, different studies on TCGA and GEO databases have demonstrated that additional lncRNAs, including PRRT3‐AS1, 26 DANCR 26 and FOXD2‐AS1, 31 are related to clinical outcomes and melanoma progression. Additionally, several studies have introduced lncRNA‐based models for predicting clinical outcomes in uveal and cutaneous melanoma patients 26,32–35 . Xu et al.…”

Identification of an Eight-Cuproptosis-related lncRNA Signature as a Novel Prognostic Model and Prediction of Immunotherapy Response in Ovarian Cancer

“…High expression of SUCLG2-AS1 is associated with better OS in clear cell renal cell carcinoma and triple-negative breast cancer(31, 32). High expression of AC245041.1 is a poor prognostic factor in patients with gastric adenocarcinoma and cutaneous melanoma (15,33). High expression of AC019080.5 is a risk factor for poor OS in patients with endometrial cancer (34, 35).…”

“…lncRNAs are involved in the mechanisms of OC progression, including carcinogenesis, proliferation, migration, invasion, metastasis, and angiogenesis (10,14). Evidence has shown that lncRNAs can participate in the development, recurrence, and response to OC immunotherapy by regulating multiple pathways, such as ferroptosis (15), autophagy (16), pyroptosis (17), necroptosis (18).…”

Identification of lncRNAs involved in response to ionizing radiation in fibroblasts of long-term survivors of childhood cancer and cancer-free controls

“…AC125807.2 was identified to be part of a network of competing endogenous RNA networks, also including TMPO-AS1 (red module; only correlated with HDIR), to regulate FAM82B expression in lung adenocarcinoma, leading to poor prognosis ( 49 ) and was overexpressed in cutaneous melanoma ( 50 ). Moreover, AC125807.2 was presented as part of a list of 14 immune-related lncRNAs which were associated with clinical outcomes in melanoma patients ( 51 ) and discussed as potentially involved in ferroptosis ( 52 ). Ferroptosis regulates cell death via lipid peroxidization, thus posing as a mechanism for tumor suppression.…”