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

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.

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.

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<0.001), whereas FOXA1 was mutually exclusive with both TMPRSS2 and ERG (q<0.001). Although FOXA1 alterations showed no significant Pearson correlation with FGA (r=-0.01, p=0.76), a moderate Spearman correlation (ρ=0.52, p<0.001) suggested enrichment in genomically unstable tumors.

FOXA1 defines a major oncogenic axis in prostate cancer, distinct from TMPRSS2-ERG fusion and PROX1 induction. Class 1 and 2 FOXA1 mutations drive alternative transcriptional programs leading to therapy resistance, highlighting FOXA1 as a critical biomarker and target for chromatin-directed interventions.