PCNA in Pan-Cancer: A Prognostic Biomarker Unveiled Through a Data-Driven, Multidimensional Analysis of Transcriptomics, Immunity, and Functional Profiling.

Proliferating cell nuclear antigen (PCNA) is a central regulator of numerous cellular processes impacting DNA metabolism and genetic integrity, including DNA damage, cell cycle progression, and transcriptional regulation. PCNA aberrations manifest in different disease phenotypes, including neoplastic proliferation, chromatin disassembly, genomic instability, and impaired DNA repair. Although the role of PCNA in control of DNA homeostasis has been extensively studied in some cancers, its pan-cancer relevance in tumorigenesis, immune interactions, and therapeutic resistance remains underexplored. Here, we undertook a comprehensive analysis of publicly available databases to assess the relationship between PCNA expression and the immunological, survival, genetic, functional, and drug sensitivity profiles across multiple cancer types. PCNA mRNA levels were altered in across cancers and associated with altered cancer signaling networks constituting Wnt, Hippo, and mTOR pathways. Increased transcript levels were associated with poor overall survival in some cancers, including ACC, CESC, LGG, and THYM. Amplification was the predominant genetic alteration of PCNA in multiple tumors. In several tumors, upregulation of PCNA was linked with differences in tumor-infiltrating lymphocytes, and specific immune-inhibitors, and chemokines. Moreover, elevated PCNA expression was linked with increased sensitivity to several drugs, particularly to Navitoclax, NPK76-II-72-1, and Ciclopirox across cancers. Our study orients the first comprehensive pan-cancer analysis of PCNA, uncovering its prognostic significance and altered expression across various cancers through multiomics data. Unlike previous studies, tumor-specific genetic alterations, such as amplification and hypomethylation, and the paradoxical immune microenvironment linked to PCNA were explored, suggesting potential immune evasion mechanisms. Additionally, new therapeutic avenues reveal PCNA's relationship with drug sensitivity to agents like Navitoclax and Ciclopirox, providing invaluable insights for pharmacological interventions.