Integrated Analysis Reveals the Prognostic Significance of Pyrimidine Metabolic Rate Limiting Enzymes in Patients with Lung Adenocarcinoma

Abstract Background: Reprogramming of metabolism is illustrated in many types of cancer and is associated with the clinical outcomes of cancer patients. However, the prognostic significance of pyrimidine metabolism signaling pathway in patients with lung adenocarcinoma (LUAD) is unclear.Methods: Using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets, we determined the prognostic significance of pyrimidine metabolic rate limiting enzymes in patients with lung cancer. The enrichment of pyrimidine metabolism signaling pathway was analyzed by gene set enrichment analysis (GSEA). The expression profiles of pyrimidine metabolic rate limiting enzymes were identified from Affymetrix gene expression data and RNA-seq data. The Kaplan-Meier Plotter was used to identify the prognostic significance of the pyrimidine metabolic rate limiting enzymes. Spearman’s correlation and multivariate cox regression were used to determine the correlation efficiency of pyrimidine metabolic rate limiting enzymes.Results: The pyrimidine metabolism signaling pathway is significantly enriched in LUAD tissues, but not in lung squamous cell carcinoma (LUSC) tissues. Compared with normal lung tissues, the pyrimidine metabolic rate limiting enzymes are highly expressed in lung tumor tissues. Furthermore, the high expression levels of pyrimidine metabolic rate limiting enzymes are associated with unfavorable prognosis in patients with LUAD. Moreover, we demonstrate that the hypo-DNA methylation, DNA amplification and TP53 mutation are contributing to the high expression levels of pyrimidine metabolic rate limiting enzymes in cancer cells. Finally, we reveal the significant connections between the pyrimidine metabolic rate limiting enzymes. Comprehensively, the pyrimidine metabolic rate limiting enzymes are highly expressed in patients with bladder cancer, breast cancer, colon cancer, liver cancer and stomach cancer. And the high expression levels of pyrimidine metabolic rate limiting enzymes are associated with unfavorable prognosis in patients with liver cancer. Conclusions: Pyrimidine metabolism signaling pathway is associated with the development of lung adenocarcinoma. Pyrimidine metabolic rate limiting enzymes CAD, DTYMK, RRM1, RRM2, TK1, TYMS, UCK2, NR5C2 and TK2 have significant prognostic effects in patients with lung adenocarcinoma.