Men With Chronic Orchialgia Exhibit Differential Neuroinflammatory Gene Expression Relative to Asymptomatic Controls.

OBJECTIVE: To identify differences in neuroinflammatory gene expression in individuals with chronic orchialgia (CO) compared to asymptomatic controls. METHODS: Vas deferens, spermatic cord fascia, blood, and urine were collected from 9 men with CO at time of microscopic spermatic cord denervation and 7 asymptomatic controls at time of vasectomy. RNA was isolated and analyzed with the NanoString Human Neuroinflammation panel. Data were normalized, gene expression fold changes and enriched pathways relative to asymptomatic controls were determined. Gene expression was considered significantly different if there was a >2-fold change and P-value <.05 relative to controls. RESULTS: Mean patient age was 51 years and median symptom duration 12 months. There were 26 genes with significantly differential expression in vas deferens. cFos, a marker of nociceptive pain, had the greatest difference (30.2-fold change, P <.000001). Enriched pathways in vas deferens included nerve function, matrix remodeling, and innate immune responses. In fascia, cFos also had the greatest differential expression (38-fold, P = .000002), followed by S100A12 (11-fold, inducer of innate immune response). Enriched pathways in fascia included nerve function and inflammation. In blood, there were no differentially expressed genes, and in urine there were 95 differentially expressed genes. CONCLUSION: Men with CO have a diverse set of neuroinflammatory genes with differential expression in tissue and urine relative to healthy controls. These findings confirm pathologic changes in tissue targeted by denervation surgery, and suggest molecular changes in neuropathic pain that could lead to biomarker identification and novel treatment.

Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment.

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9×10-7 and GAB2, p = 2.0×10-6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.

Neuroinflammatory gene expression analysis reveals potential novel mediators and treatment targets in interstitial cystitis with Hunner lesions.

BACKGROUND: We sought to study differential neuroinflammatory gene expression in men with interstitial cystitis (IC) with Hunner lesions compared with asymptomatic controls using NanoString, which uses barcoded probes to measure hundreds of genes. IC is a heterogenous condition lacking reliable biomarkers, and a subset of patients exhibits Hunner lesions, implicating the bladder as an inflammatory pain generator. METHODS: Blood, urine, and bladder biopsies were collected from 6 men with IC and Hunner lesions. 7 asymptomatic controls had blood and urine collected and 2 benign bladder biopsies were obtained from our tissue bank. RNA was isolated and analyzed with NanoString Human Neuroinflammation panel. Gene expression was considered significant if there was a >1.5-fold change and adjusted P value <0.05 compared with controls. RESULTS: Mean patient age was 61.5 years with 8 years median symptom duration. In bladder tissue, while many cytokine and chemokine genes had higher expression as expected (e.g., TNF, CXCL10), other significant genes included TRPA1 (1098-fold increased, expressed in pain sensing neurons) and TNFRSF17 (735-fold, B-cell related). In urine, there was 114-fold increase in S1PR4, which mediates pain via TRP-dependent pathways. A patient on cyclosporine had lower inflammatory gene expression levels relative to other IC patients, but no difference in TRPA1. CONCLUSIONS: Men with IC and Hunner lesions have a diverse set of neuroinflammatory genes with differential expression compared to controls. We identified genes linked to neuropathic pain through the TRP pathway and this expression was not reduced by cyclosporine. These findings open a new direction for biomarker and therapeutic discovery.