Abstract 6849: Characterizing a discernible stromal fibroblastic gene signature in the shift from high-grade prostatic intraepithelial neoplasia to aggressive prostate cancer
Authors: Alexanderani Mohammad K. , Queiroz Lucio , Omar Mohamed , Zanettini Claudio , Pakula Hubert , Marchionni Luigi , Loda Massimo 
Published: March 2024

Background: High-grade prostatic intraepithelial neoplasia (HGPIN) is a preneoplastic lesion that precedes the development of both indolent and aggressive variants of prostate cancer (PCa). However, the specific stromal molecular mechanisms underlying the progression of HGPIN and their contribution to epithelial cancer cell motility and invasiveness remain poorly understood. This study aims to elucidate the driver genomic alterations involved in shaping the perineoplastic stroma of HGPIN, with the goal of unraveling their role in promoting cancer invasion, and metastasis.

Methods: We performed gene expression profiling on laser capture microdissected perineoplastic stroma of HGPIN and PCa in tissue samples from 25 PCa cases, including 12 low-grade (Gleason 6) and 13 high-grade (Gleason &gt;/= 8) cases. We used the standard moderated t-test from the Bioconductor limma package to assess the statistical significance of differential gene expression between perineoplastic stroma high grade PCa and perineoplastic stroma HGPIN, as well as between perineoplastic stroma low grade PCa and HGPIN. The -log10 p-values represents the level of statistical significance for each gene, while the log2 fold change represents the magnitude of gene expression difference between the two comparison groups. Additionally, we computed Gene Set Enrichment Analysis (GSEA) scores using the Bioconductor package and discerned the leading-edge genes among the pathways. This study is supported by the NIH-NCI-T32 program for next-generation pathologists at our institution.

Results: In the gene expression analysis comparing High Grade PCa and HGPIN, several genes, including POSTN, BGN, GREM1, C1QA, THBS4, COL1A1, COL1A2, SFRP4, RNU6-847P, FCGR2P, and TOMM22, exhibited the highest level of both biological and statistical significance. GSEA revealed that the multi-invasive pathway had the highest enrichment score (&gt;2). Notably, the top overexpressed genes in this pathway exhibited a fibroblastic signature (in bold), including POSTN, BGN, GREM1, FBN1, COL1A2, COL3A1, COL5A2, ASPN, SPARC, VCAN, COMP, INHBA, THBS2, and SFRP4. The presence of this signature indicates the invasiveness of the disease. Importantly, these genes were not associated with the progression to low grade PCa, indicating their exclusive association with the aggressive variant.

Conclusion: To our knowledge, this study is the first to explore the stroma's role in HGPIN-to-aggressive PCa progression. It highlights a key stromal pathway enriched with fibroblastic gene signature. These findings offer potential biomarkers for targeted therapies and improved care through HGPIN patient stratification.

Citation Format: Mohammad K. Alexanderani, Lucio Queiroz, Mohamed Omar, Claudio Zanettini, Hubert Pakula, Luigi Marchionni, Massimo Loda. Characterizing a discernible stromal fibroblastic gene signature in the shift from high-grade prostatic intraepithelial neoplasia to aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6849.