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Prostate epithelial genes define therapy-relevant prostate cancer molecular subtype

 Hyunho Han  ;  Hyung Ho Lee  ;  Kwibok Choi  ;  Young Jun Moon  ;  Ji Eun Heo  ;  Won Sik Ham  ;  Won Sik Jang  ;  Koon Ho Rha  ;  Nam Hoon Cho  ;  Filippo G Giancotti  ;  Young-Deuk Choi 
 PROSTATE CANCER AND PROSTATIC DISEASES, Vol.24(4) : 1080-1092, 2021-12 
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Background and objectives: Transcriptomic landscape of prostate cancer (PCa) shows multidimensional variability, potentially arising from the cell-of-origin, reflected in serum markers, and most importantly related to drug sensitivities. For example, Aggressive Variant Prostate Cancer (AVPC) presents low PSA per tumor burden, and characterized by de novo resistance to androgen receptor signaling inhibitors (ARIs). Understanding PCa transcriptomic complexity can provide biological insight and therapeutic guidance. However, unsupervised clustering analysis is hindered by potential confounding factors such as stromal contamination and stress-related material degradation.

Materials and methods: To focus on prostate epithelial cell-relevant heterogeneity, we defined 1,629 genes expressed by prostate epithelial cells by analyzing publicly available bulk and single- cell RNA sequencing data. Consensus clustering and CIBERSORT deconvolution were used for class discovery and proportion estimate analysis. The Cancer Genome Atlas Prostate Adenocarcinoma dataset served as a training set. The resulting clusters were analyzed in association with clinical, pathologic, and genomic characteristics and impact on survival. Serum markers PSA and PAP was analyzed to predict response to docetaxel chemotherapy in metastatic setting.

Results: We identified two luminal subtypes and two aggressive variant subtypes of PCa: luminal A (Adipogenic/AR-active/PSA-high) (30.0%); luminal S (Secretory/PAP-high) (26.0%); AVPC-I (Immune-infiltrative) (14.7%), AVPC-M (Myc-active) (4.2%), and mixed (25.0%). AVPC-I and AVPC-M subtypes predicted to be resistant to ARI and have low PSA per tumor burden. Luminal A and AVPC-M predicted to be resistant to docetaxel and have high PSA/PAP Ratio. Metastatic PCa patients with high PSA/PAP ratio (>20) had significantly shorter progression-free survival than those with low ratio (≤20) following docetaxel chemotherapy.

Conclusion: We propose four prostate adenocarcinoma subtypes with distinct transcriptomic, genomic, and pathologic characteristics. PSA/PAP ratio in advanced cancer may aid in determining which patients would benefit from maximized androgen receptor inhibition or early use of antimicrotubule agents.
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1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Urology (비뇨의학교실) > 1. Journal Papers
Yonsei Authors
Rha, Koon Ho(나군호) ORCID logo https://orcid.org/0000-0001-8588-7584
Jang, Won Sik(장원식) ORCID logo https://orcid.org/0000-0002-9082-0381
Cho, Nam Hoon(조남훈) ORCID logo https://orcid.org/0000-0002-0045-6441
Choi, Young Deuk(최영득) ORCID logo https://orcid.org/0000-0002-8545-5797
Han, Hyun Ho(한현호) ORCID logo https://orcid.org/0000-0002-6268-0860
Ham, Won Sik(함원식) ORCID logo https://orcid.org/0000-0003-2246-8838
Heo, Ji Eun(허지은) ORCID logo https://orcid.org/0000-0002-4184-8468
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