Prognostic and immunotherapeutic implications of histamine-related biomarkers in lung adenocarcinoma.

Background: Recent researches have revealed that histamine plays a critical role in promoting pathogenesis of cancers. However, the key histamine-related molecular signatures and their functional roles in lung adenocarcinoma (LUAD) remain largely unknown. Methods: Differentially expressed analysis was conducted on transcriptome data to screen differentially expressed genes (DEGs) between LUAD and control (adjacent non-cancerous samples) groups. The differentially expressed histamine-related genes in LUAD were identified by intersecting DEGs and histamine-related genes. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) analyses were applied to determine key signatures associated with LUAD prognosis. Subsequently, we constructed a histamine-related prognostic risk model, compared functional enrichment and immune cell infiltration, and predicted immunotherapeutic responses and chemotherapeutic sensitivities between two risk groups using gene set enrichment analysis (GSEA), CIBERSORT, and TIDE algorithms. Finally, we investigated the expression patterns and methylation levels of key signatures. Results: Firstly, 24 candidate histamine-related genes in LUAD, which were involved in histamine transport/secretion and neurotransmitter receptor activity were identified. After univariate Cox regression and LASSO analyses, five histamine-related genes, including SLC18A2, CDT1, PLA2G3, TSPAN7 and BTK were identified as associated with LUAD prognosis. Specifically, CDT1 was up-regulated, while the other four genes were down-regulated in LUAD samples. By calculating the histamine-related risk score, a risk model with area under curve values >0.6 (up to 0.7) for 1-, 3-, and 5-year predictions in both training and validation sets was constructed and validated. Further enrichment analysis showed a relation between risk score and immune (immune cells, immunotherapy response), and we found that low-risk group was in a more immunoactive status. Importantly, low-risk patients were predicted to have better responses to immunotherapy, while high-risk group had greater sensitivity to crizotinib, docetaxel, erlotinib, gefitinib, paclitaxel and vinorelbine. Moreover, we identified that the DNA methylation profiles of these signatures were altered in LUAD. Conclusion: In this study, we focused on histamine, identified histamine-related genes and developed a new prognostic model for LUAD, providing an important theoretical foundation and practical reference for pathogenesis and precision treatment of patients with LUAD.