Crosstalk between copper homeostasis and cuproptosis reveals a lncRNA signature to prognosis prediction, immunotherapy personalization, and agent selection for patients with lung adenocarcinoma

Background: Copper homeostasis and cuproptosis play critical roles in various biological processes of cancer; however, whether they can impact the prognosis of lung adenocarcinoma (LUAD) remain to be fully elucidated. We aimed to adopt these concepts to create and validate a lncRNA signature for LUAD prognostic prediction.

Methods: For this study, the TCGA-LUAD dataset was used as the training cohort, and multiple datasets from the GEO database were pooled as the validation cohort. Copper homeostasis and cuproptosis regulated genes were obtained from published studies, and various statistical methods, including Kaplan-Meier (KM), Cox, and LASSO, were used to train our gene signature CoCuLncSig. We utilized KM analysis, COX analysis, receiver operating characteristic analysis, time-dependent AUC analysis, principal component analysis, and nomogram predictor analysis in our validation process. We also compared CoCuLncSig with previous studies. We performed analyses using R software to evaluate CoCuLncSig's immunotherapeutic ability, focusing on eight immune algorithms, TMB, and TIDE. Additionally, we investigated potential drugs that could be effective in treating patients with high-risk scores. Additionally qRT-PCR examined the expression patterns of CoCuLncSig lncRNAs, and the ability of CoCuLncSig in pan-cancer was also assessed.

Results: CoCuLncSig containing eight lncRNAs was trained and showed strong predictive ability in the validation cohort. Compared with previous similar studies, CoCuLncSig had more prognostic ability advantages. CoCuLncSig was closely related to the immune status of LUAD, and its tight relationship with checkpoints IL10, IL2, CD40LG, SELP, BTLA, and CD28 may be the key to its potential immunotherapeutic ability. For the high CoCuLncSig score population, we found 16 drug candidates, among which epothilone-b and gemcitabine may have the most potential. The pan-cancer analysis found that CoCuLncSig was a risk factor in multiple cancers. Additionally, we discovered that some of the CoCuLncSig lncRNAs could play crucial roles in specific cancer types.

Conclusion: The current study established a powerful prognostic CoCuLncSig signature for LUAD that was also valid for most pan-cancers. This signature could serve as a potential target for immunotherapy and might help the more efficient application of drugs to specific populations.