Gene expression profiles in benign prostate tissue reflect tumor proximity, grade, and molecular subtype.

BACKGROUND

Normal tissue in a tumor-bearing organ shows morphological and molecular differences from normal tissue in a tumor-free organ. One explanation to this is that tumors actively instruct adjacent normal tissues to support growth and invasion. The aim of this study was to examine if changes in gene-expression patterns in tumor-adjacent histologically benign prostate tissue, termed tumor instructed normal tissue (TINT), were associated with tumor proximity, grade and molecular subtype and, furthermore, whether they could indicate the presence of high-grade cancer elsewhere in the prostate.

METHODS

Gene-expression analysis using Clariom D microarrays was performed on matched formalin-fixed paraffin-embedded samples including tumor tissue (n = 44), benign prostate tissue taken near (TINT-N, n = 44) or distant (TINT-D, n = 42) to the tumor in 44 men with unifocal cancer treated by prostatectomy. TINT changes related to cell proliferation and immune cell infiltration were examined using immunohistochemical markers. In addition, gene expression was compared between tumor-negative biopsies from men later diagnosed with high-grade cancer (Bx-later-tumor, n = 46), tumor-negative biopsies from men who remained cancer-free (Bx-control, n = 49), and cancer-containing biopsies (Bx-tumor, n = 28). Gene set enrichment analysis (GSEA) was performed to explore hallmark gene sets in tumor and TINT tissue in relation to tumor grade (high vs. low) and molecular subtype (Luminal B vs. Luminal A).

RESULTS

The transcriptome in TINT differed significantly from that in cancer-free biopsy control tissue and was related to tumor grade (high- vs. low), molecular subtype (Luminal B vs. Luminal A), and tumor proximity (TINT-N vs. TINT-D). Hallmarks related to cell proliferation and increased Ki67 staining as well as signs of increased metabolism were generally enriched in both tumor and TINT tissue of high grade and Luminal B tumors. In contrast, some immune responses were unique to TINT areas of high-grade and Luminal A tumors, respectively, and more obvious in TINT-N than in TINT-D. Analysis of Bx-later-tumor indicated enriched metabolism compared to Bx-control, without clear proliferative or immunological differences.

CONCLUSIONS

TINT effects involving proliferation, metabolism and immune responses are related to distance, tumor grade and molecular subtype. TINT alterations hold potential as diagnostic and prognostic biomarkers and may provide a basis for further exploration of tumor-host interactions and potential targets for intervention.