Urine miRNA Biomarkers that are Differentially Expressed in Lichen Sclerosus Induced and Non-Lichen Sclerosus Induced Urethral Stricture Disease
Karl Benz, MD, Travis Sullivan, MS, Thomas Kalantzakos, BA, Amanda Sherman, MD, Harjivan Kohli, MD, Eric Burks, MD, Kimberly Rieger-Christ, PhD, Alex Vanni, MD.
Lahey Hospital and Medical Center, Burlington, MA, USA.
BACKGROUND: Identifying non-invasive biomarkers that distinguish Lichen Sclerosus (LS) induced from non-LS induced urethral strictures would have broad implications for the diagnosis, counseling, and treatment of urethral stricture disease (USD). The objective of this study is to determine which miRNAs are differentially expressed in urine samples from patients with LS USD versus non-LS USD. METHODS: A prospectively maintained institutional USD database of patients who underwent urethroplasty was queried for patients with an available pre-operative voided urine sample obtained between July 2018 and February 2020. Urine miRNA were analyzed in patients with and without histologically confirmed LS USD. Total RNA was isolated and reverse transcribed from each urine supernatant sample. miRNA expression was then profiled using RT-qPCR arrays for 376 unique miRNAs. Urine samples were excluded if there was recent catheterization, if the urine was obtained from a suprapubic tube, or if the patient had a history of hypospadias. RESULTS: In total, 24 patients met inclusion criteria, 14 (58%) of which were post-operatively histologically classified as having LS. There were no significant differences between the LS and non-LS USD groups regarding patient age, body mass index, history of smoking, or history of diabetes mellitus. Of the 376 miRNAs tested, forty-five unique miRNAs were differentially expressed in LS urines (p<0.05), 4 of which had a p-value of <0.01. Of those four, miR-186-5p (p=0.002, AUC 0.736) and miR-185-5p (p=0.003, AUC 0.764) were upregulated in LS, while miR-153-3p (p=0.005, AUC 0.701) and miR-509-3p (p=0.006, AUC 0.688) were downregulated (Figure 1). CONCLUSIONS: This is the first study to demonstrate unique urine miRNA that distinguish LS from non-LS USD. This discovery could be used to create a non-invasive urine test to distinguish the LS vs non-LS USD, therefore obviating the need for biopsy. The two most promising candidates, miRNAs 185-5p and 186-5p, have been shown to mediate the androgen receptor, fibrosis pathways, and cell proliferation pathways. Further investigation is needed to validate these findings in a larger cohort.
Figure 1: Relative expression levels of the top four microRNA differentially expressed in the urine of LS patients.
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