Identification of tumor-agnostic biomarkers for predicting prostate cancer progression and biochemical recurrence

Abstract

The diverse clinical outcomes of prostate cancer have led to the development of gene signature assays predicting disease progression. Improved prostate cancer progression biomarkers are needed as current RNA biomarker tests have varying success for intermediate prostate cancer. Interest grows in universal gene signatures for invasive carcinoma progression. Early breast and prostate cancers share characteristics, including hormone dependence and BRCA1/2 mutations. Given the similarities in the pathobiology of breast and prostate cancer, we utilized the NanoString BC360 panel, comprising the validated PAM50 classifier and pathway-specific signatures associated with general tumor progression as well as breast cancer-specific classifiers. This retrospective cohort of primary prostate cancers (n=53) was stratified according to biochemical recurrence (BCR) status and the CAPRA-S to identify genes related to high-risk disease. Two public cohort (TCGA-PRAD and GSE54460) were used to validate the results. Expression profiling of our cohort uncovered associations between PIP and INHBA with BCR and high CAPRA-S score, as well as associations between VCAN, SFRP2, and THBS4 and BCR. Despite low levels of the ESR1 gene compared to AR, we found strong expression of the ER signaling signature, suggesting that BCR may be driven by ER-mediated pathways. Kaplan-Meier and univariate Cox proportional hazards regression analysis indicated the expression of ESR1, PGR, VCAN, and SFRP2 could predict the occurrence of relapse events. This is in keeping with the pathways represented by these genes which contribute to angiogenesis and the epithelial-mesenchymal transition. It is likely that VCAN works by activating the stroma and remodeling the tumor microenvironment. Additionally, SFRP2 overexpression has been associated with increased tumor size and reduced survival rates in breast cancer and among prostate cancer patients who experienced BCR. ESR1 influences disease progression by activating stroma, stimulating stem/progenitor prostate cancer, and inducing TGF-β. Estrogen signaling may therefore serve as a surrogate to AR signaling during progression and in hormone-refractory disease, particularly in prostate cancer patients with stromal-rich tumors. Collectively, the use of agnostic biomarkers developed for breast cancer stratification has facilitated a precise clinical classification of patients undergoing radical prostatectomy and highlighted the therapeutic potential of targeting estrogen signaling in prostate cancer.

Investigating the Role of SNAI1 and ZEB1 Expression in Prostate Cancer Progression and Immune Modulation of the Tumor Microenvironment

“…The Faculty of Medicine at the Ribeirão Preto (FMRP) cohort comprised 51 primary prostate cancer samples obtained via radical prostatectomy, in accordance with the National Comprehensive Cancer Network (NCCN) clinical practice guidelines [27], at the Urology Division of the Department of Surgery and Anatomy, FMRP-USP, Brazil, between 2007 and 2015 (Table S1). Transcriptomic data derived from this cohort were recently included in another publication by our group [28]. Smaller prostates were submitted for pathological assessment in their entirety according to the guidelines of the American College of Pathology.…”

“…Additionally, we categorized the expression levels of ZEB1 and SNAI1 into quartiles for each gene. These categorical data allowed us to classify patient gene expressions as either "low" (below Q3) or "high" (above Q3) for ZEB1 and SNAI1 [28]. We then used the classification status of ZEB1 and SNAI1 as the design factor for the transcriptome analysis as described earlier.…”