Multiomics analysis identifies RNASET2 as a potential candidate target associated with lung adenocarcinoma

Abstract

Objective Lung cancer is the leading cause of cancer-related mortality worldwide, with lung adenocarcinoma representing the predominant subtype. The increasing incidence of lung adenocarcinoma underscores the urgent need to establish novel therapeutic targets for clinical intervention. Methods We performed Mendelian randomization and colocalization analyses on large-scale lung adenocarcinoma genome-wide association study datasets. Bulk transcriptome and single-cell RNA sequencing were further applied to explore the function of candidate targets and related cell types. Results Mendelian randomization revealed that elevated RNASET2 expression causally reduced the risk of lung adenocarcinoma (odds ratio = 0.817, 95% confidence interval: 0.754–0.885, p < 0.001), whereas increased BTN3A2 expression was associated with an elevated disease risk. Colocalization analysis supported a shared causal variant between RNASET2 and lung adenocarcinoma (posterior probability of hypothesis 4 = 78.6%). Bulk transcriptome data demonstrated that RNASET2 was upregulated in tumor tissues and was associated with better prognosis. Single-cell RNA sequencing revealed that macrophages were the predominant cell type expressing RNASET2, whereas weak expression was also detected in pulmonary epithelial cells and several other cell populations. There was a trend toward reduced abundance of high RNASET2-expressing macrophage subcluster 0 in tumor tissues, whereas low RNASET2-expressing subcluster 8 tended to accumulate within tumor lesions. Enrichment analysis of their signature genes suggested opposing biological roles in lung adenocarcinoma progression, which warrants further functional verification. Conclusions RNASET2 is closely associated with the occurrence and prognosis of lung adenocarcinoma. Macrophage-expressed RNASET2 represent a promising candidate molecule for further therapeutic exploration.