Background: Tumor microenvironment and its interaction with neuroendocrine modulators contribute to prostate carcinogenesis and progression. Objective: We sought to define the transcriptomic and clinical implications of neuropeptide Y (NPY) expression in prostate cancer progression. Design, setting, and participants: Genome-wide expression profiling of three localized prostate cancer (total n = 18 818) and five metastatic castrate-resistant prostate cancer (mCRPC; total n = 495) cohorts was used to characterize NPY expression. All men underwent radical prostatectomy (RP) for localized prostate cancer. Outcome measurements and statistical analysis: Patients were grouped into those with low NPY and high NPY based on NPY expression. Associations between these groups and histological, genomic, and clinical outcomes including progression-free survival (PFS) and metastases-free survival (MFS) were examined. Combining ERG-fusion status with NPY expression, four groups were defined (lowNPY/ERG+, lowNPY/ERG−, highNPY/ERG+, and highNPY/ERG−). Cox proportional hazards modeled the time to distant metastasis after RP. Genomic risk scores for metastasis were calculated for prospective samples, based on a 22-gene signature. Results and limitations: Across cancers, NPY showed the highest expression in prostate cancer in The Cancer Genome Atlas (TCGA) PAN-Cancer cohort (n = 9483, p < 0.0001). In 17 967 prospective samples, low NPY expression was associated with aggressive grade group 5 disease and a higher genomic risk (p < 0.0001). In the retrospective (n = 355) and TCGA (n = 497) cohorts, low NPY was associated with shorter MFS and PFS, respectively (p = 0.001 for both). In mCRPC cohorts, low NPY was associated with neuroendocrine development (p < 0.01). NPY was highly correlated to ERG; thus, we defined four groups based on NPY expression and ERG fusion. The lowNPY/ERG+ subtype was associated with the highest genomic risk for metastasis (p < 0.0001) and the highest rate of metastasis compared with all other subtypes (hazard ratio [HR]: 2.2 [1.22–4.03], p = 0.008), while the highNPY/ERG− subtype was associated with the lowest genomic risk for metastasis (p < 0.0001) and the lowest rate of metastasis (HR: 0.53 [0.35–0.81], p = 0.003). Conclusions: Low NPY expression is associated with adverse genomic features and clinical correlates and outcomes. The lowNPY/ERG+ subtype was associated with the highest risk of developing metastasis. Prognostic subgrouping and tailored treatments by NPY expression and ERG fusion status warrant further study. Patient summary: The low neuropeptide Y prostate cancer subtype appears to be aggressive with a high risk of developing metastasis.
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