Bulk and single-cell transcriptomics reveal prognostic signatures of phosphoinositide metabolism in lung adenocarcinoma

Abstract

Abstract Lung adenocarcinoma (LUAD) is one of the most severe malignant tumors. Phosphoinositides metabolism (PIM) plays an important role in maintaining the normal life activities of the organism and regulating tumor development. This study aimed to comprehensively investigate the association between LUAD and PIM. Data on LUAD and PIM-related genes (PIM-RGs) were sourced from public databases. Differential expression, univariate Cox regression analyses, and machine learning were conducted to identify prognostic genes. A risk model was subsequently developed, and LUAD patients were categorized into a high-risk group (HRG) and a low-risk group (LRG). Independent prognostic factors for LUAD were identified, and a nomogram was constructed. Functional enrichment, tumor microenvironment, mutations, and drug sensitivity analyses were also conducted to investigate the molecular mechanisms underlying LUAD. Additionally, single-cell RNA sequencing (scRNA-seq) data analysis was employed to identify key cells and clarify the dynamics of prognostic genes’ expression. Ultimately, prognostic gene expression was investigated in clinical samples. MTMR7, GDPD1, MTMR4, and MTMR10 were recognized as prognostic genes. The risk model and nomogram (incorporating risk score and Stage) had good predictive performance. Notably, LUAD’s malignant progression might be closely associated with biological processes including cellular protein synthesis, abnormal activation of neuroactive ligand-receptor interactions, and anti-tumor immune responses. Additionally, there was a general positive correlation between the differentially infiltrated immune cells of HRG and LRG. Moreover, TP53 and TTN had relatively high mutation frequencies in both HRG and LRG, and 142 drugs exhibited differential sensitivity between the 2 groups. Interestingly, epithelial cells were identified as LUAD’s key cell type, with prognostic gene expression showing dynamic changes as these cells differentiated. Consistently, compared with the control group, GDPD1 and MTMR4 were upregulated, MTMR10 was downregulated, and MTMR7 showed no statistical difference but a certain upward trend in the LUAD group. This study identified 4 prognostic genes and constructed an effective risk model, providing a new perspective on the treatment of LUAD.