Mutational Landscape and Regulatory Network Analysis of TP53 and FOXA1 in Prostate Cancer

Abstract

Prostate cancer is a major global health burden. According to GLOBOCAN 2022 estimates, it accounts for nearly 396,792 deaths and 1,466,680 cases annually. Despite advances in immunotherapy, hormone therapy, radiation, chemotherapy, and surgery, improved biomarkers for early detection and targeted treatment remain urgently needed. In this study, cancer genomics data from cBioPortal were analyzed to identify key gene mutations associated with prostate cancer progression. Examination of 12,741 nonoverlapping samples across 28 studies revealed diverse mutation frequencies among major driver genes. Among these, TP53 and FOXA1 showed the highest numbers of somatic mutations, at 3101 (frequency 25.6%) and 1386 (frequency 11.4%), respectively, with mutation hotspots concentrated in the p53 DNA-binding and FOXA1 forkhead domains. Missense mutations were the predominant alteration type, particularly in TP53, where they may disrupt tumor suppressor activity. FOXA1 mutations, observed in primary and metastatic castration-resistant prostate cancer, were associated with aggressive disease phenotypes and potential therapeutic resistance. Survival analysis revealed that TP53 mutations were significantly associated with poorer overall survival, whereas FOXA1 mutation status was not. Clinical analysis revealed higher nonsynonymous tumor mutational burden in TP53- and FOXA1-mutant tumors than in their wild-type counterparts. Protein–protein interactions between MDM2 and EP300 with TP53 and between GATA3 and FOXA1 highlighted their roles in transcriptional regulation and prostate cancer biology. Collectively, these findings highlight TP53 and FOXA1 as promising biomarkers and potential therapeutic targets in prostate cancer. Received: 2 May 2026 | Revised: 14 July 2026 | Accepted: 4 August 2026 Conflicts of Interest The authors declare that they have no conflicts of interest to this work. Data Availability Statement Data sharing is not applicable to this article as no new data were generated or analyzed during the current study. Author Contribution Statement Shrijee Lakshkar: Validation, Formal analysis, Investigation, Writing – original draft. Pratha Tiwari: Validation, Formal analysis, Investigation, Writing – original draft. Heenal Bhatt: Investigation, Writing – original draft. Vipin Ranga: Methodology, Validation, Formal analysis, Investigation, Data curation, Writing – original draft, Writing – review & editing, Visualization. Narendra Kumar Sharma: Investigation, Writing – original draft, Writing – review & editing, Supervision. Tikam Chand Dakal: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing – original draft, Writing – review & editing, Visualization, Supervision, Project administration.