Mohammed Alshalalfa1, Paul L Nguyen2, Himisha Beltran2, William S Chen3, Elai Davicioni4, Shuang G Zhao5, Timothy R Rebbeck6, Edward M Schaeffer7, Tamara L Lotan8, Felix Y Feng9, Brandon A Mahal2. 1. Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA; Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA. Electronic address: mohamed.alshalalfa@gmail.com. 2. Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA. 3. Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA. 4. GenomeDx Biosciences Inc, Vancouver, British Columbia, Canada. 5. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. 6. Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA; Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA. 7. Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 8. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 9. Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA; Department of Urology, University of California San Francisco, San Francisco, CA, USA.
Abstract
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=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. 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 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). 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.
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=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. 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 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). 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 Yprostate cancer subtype appears to be aggressive with a high risk of developing metastasis.
Authors: Brandon A Mahal; Mohammed Alshalalfa; Shuang G Zhao; Himisha Beltran; William S Chen; Fallon Chipidza; Elai Davicioni; R Jeffrey Karnes; Sheng-Yu Ku; Tamara L Lotan; Vinayak Muralidhar; Timothy R Rebbeck; Edward M Schaeffer; Daniel E Spratt; Felix Y Feng; Paul L Nguyen Journal: Cancer Date: 2020-01-06 Impact factor: 6.860
Authors: Dawid Sigorski; Jacek Gulczyński; Aleksandra Sejda; Wojciech Rogowski; Ewa Iżycka-Świeszewska Journal: Front Oncol Date: 2021-07-01 Impact factor: 6.244