Purine and pyrimidine metabolism regulatory gene signature predicts prognosis and immunotherapy efficiency in breast cancer

Abstract BACKGROUND Breast cancer (BC) is a heterogeneous disease with diverse molecular features and outcomes. Purine and pyrimidine (PP) metabolism provide sufficient nucleotides for tumor growth. Thus, the relationship between PP metabolism and BC needs a thorough exploration. METHODS Based on the 115 PP genes and BC multi-omics data, we performed consensus clustering and functional enrichment analyses to explore the biological characteristic. After the LASSO regression and multi-Cox regression analyses, a PP gene-related signature was developed. Moreover, data from the GSE45255, GSE21653, and GSE118389 cohorts, analyses included immunophenoscore (IPS) and single-cell RNA sequencing were employed to validate the predictability. Additionally, drug sensitivity and a comprehensive nomogram were explored for clinical practice. RESULTS PP genes were predominantly enriched in pathways related to immune stimulation, tumor aggressiveness, and EMT development. We identified three BC subtypes that possess different outcomes and immunological characteristics. We constructed an eleven-gene signature (SHCBP1, SSBP2, EIF4EBP1, FHL5, ACTL8, KLF9, IGKC, SEMA3B, CXCL1, CSTA, and IGLL5) that can be effectively for risk stratification, and was positively correlated with most T cell exhaustion-related genes ( P < 0.05). The low-risk group possessed a better tumor microenvironment ( P < 0.001), a higher expression level of immune checkpoint genes ( P < 0.05), and showed immunotherapy benefits ( P < 0.05). In addition, immune infiltrating cells demonstrated a characteristic distribution between the different risk groups (P < 0.05). Notably, patients with low-risk scores showed higher sensitivity to targeted drugs (veliparib, olaparib, and palbociclib), as well ( P < 0.001). CONCLUSION PP metabolism regulatory gene signature suggests that patients assessed as low-risk have a better prognosis, immune microenvironment, and immunotherapy responses. It also inspired the exploration of biomarkers and provided novel strategies for clinical practice.