Abstract
Tumor microenvironment and its interaction with neuroendocrine modulators contribute to prostate carcinogenesis and progression.
We sought to define the transcriptomic and clinical implications of neuropeptide Y (NPY) expression in prostate cancer progression.
Genome-wide expression profiling of three localized prostate cancer (total n=18818) 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.
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.
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 17967 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).
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.
The low neuropeptide Y prostate cancer subtype appears to be aggressive with a high risk of developing metastasis.
Herein, we characterize the clinical role of neuropeptide Y (NPY) that is prostate specific in >18000 primary prostate adenocarcinomas, and >300 metastatic castrate-resistant prostate cancer (mCRPC) and treatment-induced neuroendocrine carcinomas.
We first show that low NPY is associated with higher Gleason grade tumors, higher genomic risk scores, and poorer metastasis-free survival in primary tumors. In mCRPC, low NPY was associated with neuroendocrine development.
ERG was highly correlated to NPY. Thus, we defined four subgroups based on NPY expression and ERG fusion (lowNPY/ERG+, lowNPY/ERG−, highNPY/ERG+, and highNPY/ERG−). The lowNPY/ERG+ subtype was associated with the highest genomic risk for metastasis and the highest rate of metastasis compared with all other subtypes across multiple cohorts. Differential gene expression showed that genes downregulated in lowNPY/ERG+ are enriched with androgen receptor targets. Prognostic subgrouping and tailored treatments by NPY expression and ERG fusion status warrant further study.
