Comprehensive Spatial Transcriptomic Profiling of Cribriform, Intraductal, Atypical Intraductal Proliferation, and Ductal Adenocarcinoma of the Prostate.

PURPOSE: Cribriform 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. We analyzed their gene expression using spatial transcriptomics.

MATERIALS AND

METHODS

A tissue microarray of 18 formalin-fixed paraffin-embedded cores from 17 prostatectomies was profiled for expression of 18,676 messenger RNAs using the Bruker GeoMx Digital Spatial Profiler platform. In total, 53 areas of interest were selected based on hematoxylin and eosin staining, PIN 4 immunohistochemistry, and fluorescent 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 (range, 18-130) months, 31% developed metastases. A total of 16 tumors showed mixed morphology. Three DACs had adjacent intraductal components with preserved basal cells (ductal IDC-P). Nine out of 10 acinar IDC-P and 6 out of 7 AIP presumably represented intraductal spread (invasive type); 1 was mostly noninvasive (95% IDC-P/AIP, putative precursor type). Cribriform AAC, acinar IDC-P, and AIP demonstrated substantial transcriptomic similarity, with only 4 differentially expressed genes between acinar IDC-P and cribriform AAC and between acinar IDC-P and AIP. Cribriform 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 cribriform AAC. AIP showed reduced G protein-coupled receptor signaling versus IDC-P and cribriform 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 the invasive type. DAC was transcriptomically more similar to cribriform AAC than to non-cribriform AAC. Ductal IDC-P downregulated luminal epithelial programs and upregulated antigen presentation/immune signaling versus DAC.

CONCLUSIONS

Cribriform AAC, acinar IDC-P, and AIP demonstrated substantial transcriptomic similarity despite distinct differences. DAC showed greater transcriptomic similarity to cribriform AAC than to non-cribriform AAC.