Downregulation of ANPEP Is Associated with Aggressive Prostate Cancer and Poor Disease-specific Outcomes.

[BACKGROUND AND OBJECTIVE] Aminopeptidase N (ANPEP) is linked to malignancy in certain tumor types, but its role in aggressive prostate cancer (PCa) is less well defined. Our aim was to characterize ANPEP expression in various PCa stages to determine whether it is a robust prognostic biomarker of aggressive disease.

[METHODS] We established baseline ANPEP expression in benign prostate tissue using multiple large databases. Next, we determined the association between ANPEP expression and various clinicopathologic features and molecular subtypes using ∼170 000 tumor samples from the GRID registry. We calculated median expression values, and reported standardized mean differences. We used receiver operating characteristic and Cox regression analyses to evaluate the diagnostic and prognostic significance of ANPEP for several endpoints, and performed preranked gene set enrichment analysis (GSEA) to identify biological pathways over-represented by race or ANPEP category according to hallmark gene sets.

[KEY FINDINGS AND LIMITATIONS] ANPEP expression was higher in normal prostate tissues than in prostate tumors. Advanced clinical stage, higher National Comprehensive Cancer Network risk category, and worse Gleason grade group were all associated with lower median ANPEP expression. Genomic markers of aggressive PCa, such as high Decipher scores, low androgen receptor (AR) activity, overexpression, and loss of expression, were correlated with lower ANPEP expression. Among patients with locally advanced or metastatic PCa, higher ANPEP expression was significantly associated with more favorable PCa-specific outcomes, including biochemical recurrence, distant metastasis, castration-resistant PCa, and overall survival. GSEA revealed AR upregulation for the ANPEP-high group and men with genomic-derived African race. Conversely, the G-M DNA damage checkpoint and target genes were enriched in the ANPEP-low and genomic-derived European race groups.

[CONCLUSIONS AND CLINICAL IMPLICATIONS] Our findings show that ANPEP downregulation is linked to a more aggressive PCa phenotype. Higher ANPEP levels were associated with more favorable outcomes, thereby, establishing ANPEP expression as a prognostic factor for treatment response.

[PATIENT SUMMARY] We looked at levels of a protein called aminopeptidase N (ANPEP) in prostate tumors using information from large databases. We found that ANPEP is linked to markers that indicate more aggressive disease and that higher ANPEP levels are associated with more favorable treatment outcomes.