Spatial Transcriptomic Profiling to Characterize the Nature of Peripheral- Versus Transition-zone Prostate Cancer.

Abstract

Background and objective: Prostate cancer (PC) in the transition zone (TZ) has better prognosis than peripheral-zone (PZ) PC despite higher prostate-specific antigen (PSA) in patients with TZ tumors. Our aim was to characterize molecular differences between TZ and PZ tumors and their clinical implications.

Methods: We performed spatial whole-transcriptome analyses of 50 regions of interest (ROIs) from three patients with PZ and/or TZ PC. ROIs were selected on the basis of SYTO13, pan-cytokeratin, smooth muscle actin, and CD45 markers. Downstream analyses of the transcriptomics data included differential gene expression and Molecular Signatures Database cancer hallmark analysis for pathway enrichment. Survival analyses were performed in The Cancer Genome Atlas (TCGA) prostate data set.

Key findings and limitations: We analyzed Gleason grade 4 (10 ROIs) and grade 5 (10 ROIs) tumors from the PZ, and grade 3 (10 ROIs), grade 4 (11 ROIs), and grade 5 (1 ROI) tumors from the TZ. We observed distinct gene expression profiles between PZ (n = 20) and TZ (n = 22) tumors. TZ ROIs exhibited enrichment of androgen response signaling (ARS; false discovery rate <5%) and a higher androgen subscore of the genomic prostate score (p < 0.001), regardless of grade and the epithelial, stromal, or immune component of the region. Genes underexpressed in PZ tumors, including ARS genes, were associated with poorer progression-free survival in the TCGA data set (n = 451; p < 0.05).

Conclusions and clinical implications: Our results demonstrate higher ARS in TZ tumors than in PZ tumors, explaining the higher PSA and better prognosis for TZ tumors. Further studies are needed to integrate zonal location in diagnostic and treatment algorithms for PC.

Patient summary: We looked at the biological explanation for higher PSA (prostate-specific antigen) levels in blood for cancers found in different zones of the prostate. We found that genes involved in androgen response signaling may explain the higher PSA often seen for tumors in the transition zone than for tumors in the peripheral zone of the prostate. These findings may inform how we diagnose and treat prostate cancer.