The Prostate Stromal Transcriptome in Aggressive and Lethal Prostate Cancer.

TitleThe Prostate Stromal Transcriptome in Aggressive and Lethal Prostate Cancer.
Publication TypeJournal Article
Year of Publication2023
AuthorsMa C, Zhou Y, Fanelli GNicolò, Stopsack KH, Fiorentino M, Zadra G, Mucci LA, Loda M, Tyekucheva S, Penney KL
JournalMol Cancer Res
Date Published2023 Mar 01
KeywordsBiomarkers, Tumor, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Humans, Male, Neoplasm Grading, Prostate, Prostatic Neoplasms, Transcriptome, Tumor Microenvironment

Prostate cancer has a heterogeneous prognosis. Most previous studies have focused on the identification of prognostic biomarkers in the prostate cancer tumor. However, it is increasingly recognized that the tumor microenvironment contributes to prostate cancer aggressiveness and progression. We therefore examined whole transcriptome expression of the prostate stroma and associations with aggressive and lethal prostate cancer. We performed RNA sequencing (Illumina TruSeq Exome Capture) of 272 tumor-adjacent and 120 benign-adjacent macrodissected prostate stromal samples from 293 men with prostate cancer from the Health Professionals Follow-up Study and Physicians' Health Study. We performed differential expression analysis comparing gene expression and pathways by Gleason score and lethal outcome. We also tested a previously developed stromal gene signature of Gleason score in these datasets. Comparing high- with low-Gleason score cancers, 26 genes (P < 0.001) and 12 pathways (FDR < 0.20) were significantly differentially expressed in tumor-adjacent stroma, including pathways related to stroma composition remodeling and DNA repair, with 73 genes and 65 pathways significant in benign-adjacent stroma. Comparing lethal with nonlethal prostate cancer, 11 genes were differentially expressed in tumor-adjacent and 15 genes in benign-adjacent stroma, and pathways involved in inflammatory response were differentially enriched in both tumor and benign-adjacent stroma. In addition, our previously identified Gleason stromal gene signature was validated to be associated with Gleason score in these data. Implications: Our study uncovers stroma-specific genes and pathways that are differentially enriched with high Gleason score and lethal prostate cancer, demonstrating that the molecular investigation of the tumor microenvironment can provide additional information about prostate cancer prognosis.

Alternate JournalMol Cancer Res
PubMed ID36511902
PubMed Central IDPMC9991973
Grant ListR37 CA227190 / CA / NCI NIH HHS / United States
U01 CA167552 / CA / NCI NIH HHS / United States
Related Faculty: 
Massimo Loda, M.D.

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