Prostate epithelial genes define therapy-relevant prostate cancer molecular subtype

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Prostate cancer (PCa) exhibits significant transcriptomic variability, impacting drug sensitivities and treatment outcomes.
• Aggressive Variant Prostate Cancer (AVPC) often shows resistance to androgen receptor inhibitors (ARIs) and low PSA levels relative to tumor burden.
• Understanding PCa transcriptomic complexity is crucial for biological insight and therapeutic guidance, but challenges like stromal contamination exist.

Purpose of the Study:

• To delineate prostate epithelial cell-specific heterogeneity in PCa.
• To identify distinct PCa subtypes based on transcriptomic profiles.
• To associate these subtypes with clinical characteristics, drug sensitivities, and patient survival.

Main Methods:

• Defined 1,629 prostate epithelial cell-expressed genes from bulk and single-cell RNA sequencing data.
• Employed consensus clustering and CIBERSORT deconvolution for class discovery.
• Utilized The Cancer Genome Atlas Prostate Adenocarcinoma dataset for training and analysis of clinical, pathologic, genomic, and survival data.

Main Results:

• Identified four PCa subtypes: Luminal A (30.0%), Luminal S (26.0%), AVPC-I (14.7%), and AVPC-M (4.2%), with mixed subtypes comprising 25.0%.
• AVPC-I and AVPC-M subtypes demonstrated predicted resistance to ARIs and low PSA per tumor burden.
• Luminal A and AVPC-M subtypes were predicted resistant to docetaxel; a high PSA/PAP ratio (>20) in metastatic PCa correlated with shorter progression-free survival after docetaxel.

Conclusions:

• Proposed four distinct prostate adenocarcinoma subtypes characterized by unique transcriptomic, genomic, and pathologic features.
• The PSA/PAP ratio may serve as a predictive biomarker for guiding treatment decisions in advanced PCa.
• This classification aids in selecting patients who may benefit from intensified androgen receptor inhibition or early antimicrotubule agent use.