FOXA1 Alterations in Prostate Cancer: Expression, Mutation Classes, and Copy Number Changes

Background/Aim: Prostate cancer features profound transcriptional dysregulation within the androgen receptor (AR) signaling axis. The pioneer factor FOXA1, which facilitates AR binding to chromatin, is recurrently altered in 10-40% of tumors. Recent studies classify FOXA1 mutations as Class 1 Wing 2 mutations, which enhance AR-dependent tumorigenesis, and Class 2 C-terminal truncations, which promote lineage plasticity and therapy resistance. The interplay of FOXA1 alterations with TMPRSS2-ERG fusions and PROX1 remains incompletely understood. Materials and Methods: Data from The Cancer Genome Atlas (TCGA) Prostate Adenocarcinoma (PRAD) cohort (n=492) were analyzed via UCSC Xena and cBioPortal. FOXA1 mutations were categorized following Eyunni et al. Copy number was assessed by log2(tumor/normal) ratios. Mutual exclusivity and co-occurrence were evaluated using Fisher’s exact test with false-discovery-rate correction. Associations between FOXA1 status and genomic instability were assessed using the fraction genome altered (FGA) metric. Results: FOXA1 was broadly expressed, with subsets showing elevation. Class 1 mutations localized to the Wing 2 region, while Class 2 truncations clustered in the C-terminal domain. Copy number changes were infrequent, indicating mutation-driven reprogramming as the main oncogenic mechanism. TMPRSS2 and ERG strongly co-occurred (log2 OR >3, q