Comprehensive Spatial Transcriptomic Profiling of Cribriform, Intraductal, Atypical Intraductal Proliferation, and Ductal Adenocarcinoma of the Prostate.
PURPOSE Cribriform (Crib) acinar adenocarcinoma (AAC), intraductal carcinoma of the prostate (IDC-P), atypical intraductal proliferation (AIP) and ductal adenocarcinoma (DAC) are linked to poor outcomes in prostate cancer (PCa). We analyzed their gene expression using spatial transcriptomics. MATERIALS AND METHODS A tissue microarray of 18 FFPE cores from 17 prostatectomies was profiled for expression of 18,676 mRNAs with the Bruker GeoMx Digital Spatial Profiler platform. 53 areas of interest were selected based on H&E, PIN4 IHC and fluorescence markers. Gene set enrichment analysis was conducted for Reactome gene sets. RESULTS Most patients had grade group ≥3 (94%) and ≥pT3 disease (65%). At a median follow-up of 47 months (range, 18-130), 31% developed metastases. 16 tumors showed mixed morphology. 3 DACs had adjacent intraductal components with preserved basal cells (ductal IDC-P). 9/10 acinar IDC-P and 6/7 AIP presumably represented intraductal spread (invasive type); one was mostly non-invasive (95% IDC-P/AIP, putative precursor type). Crib AAC, acinar IDC-P, and AIP demonstrated substantial transcriptomic similarity, with only 4 differentially expressed genes between acinar IDC-P and crib AAC and between acinar IDC-P and AIP. Crib AAC exhibited Notch signaling and homologous recombination DNA repair enrichment versus low-grade AAC. Acinar IDC-P upregulated GADD45G/ERRFI1 and downregulated CCN3/TMEFF2, with reduced PKN1-mediated androgen receptor signaling versus crib AAC. AIP showed reduced GPCR signaling versus IDC-P and crib AAC. Acinar IDC-P upregulated TSPAN8/CA4, and downregulated TRPM8/DHCR24 versus AIP. Putative precursor-type IDC-P/AIP downregulated oncogenic and stemness programs versus invasive type. DAC was transcriptomically more similar to crib AAC than to non-crib AAC. Ductal IDC-P downregulated luminal epithelial programs, and upregulated antigen presentation/immune signaling versus DAC. CONCLUSIONS Crib AAC, acinar IDC-P, and AIP demonstrated substantial transcriptomic similarity despite distinct differences. DAC showed greater transcriptomic similarity to crib AAC than to non-crib AAC.