Gene expression pathways of high grade localized prostate cancer

Background: Despite advances in screening and local therapy, prostate cancer remains the second most common cause of cancer related death among American men, with those having high grade disease being at highest risk for prostate cancer mortality. Here we identify the genes and cellular pathways that distinguish high grade from low grade pathologically localized prostate cancer.

Methods: Cancer cells from low grade (Gleason 3 + 3 = 6) or high grade (4 + 4 = 8) tumors of men with localized disease were isolated by laser capture micro-dissection. Expression profiling was conducted across 18,344 unique annotated genes and data were analyzed using packages from the R/Bioconductor project to determine differential gene expression and perform gene set enrichment analysis. Publically available expression data was retrieved and analyzed individually in the same manner and in cross platform meta-analyses.

Results: Six hundred seventy genes were differentially expressed between Gleason sum 6 and 8 tumors with a false discovery rate of <5% (P < 0.0014) including genes previously shown to mediate prostate cancer survival, proliferation, and metastasis. Functional themes associated with Gleason grade included developmental processes, signal transduction, chemokine and embryonic stem cell pathways with specific enrichment of the androgen receptor, EGFR, TNF-alpha, and Notch signaling cascades.

Conclusions: In addition to androgen receptor signaling, growth factor, and cytokine mediated pathways are active in clinically localized high grade prostate cancer. The availability of therapeutics that selectively target these pathways encourages the development of clinical trials for their selective use in the neoadjuvant or adjuvant setting in men at high risk for disease progression.