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Transcriptomic analysis reveals distinct molecular pathways in lichen sclerosus-related urethral stricture disease
Amy Zheng, MD1, Lingge Yu, MS2, Jennifer Beane-Ebel, PhD2, Eric Burks, MD3, Travis Sullivan, MS1, Kimberly Rieger-Christ, PhD1, Alex Vanni, MD1.
1Lahey Hospital & Medical Center, Burlington, MA, USA, 2Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA, 3Boston Medical Center, Boston, MA, USA.
BACKGROUND: Lichen sclerosus (LS) is associated with more complex urethral stricture disease (USD) and higher recurrence rates following urethroplasty. However, molecular mechanisms driving LS-associated epithelial remodeling remain unclear. This study aims to identify differential gene expression in USD patients with and without LS.
METHODS: Urethral tissue was collected from LS and non-LS patients at the time of USD surgery and profiled by mRNA sequencing. High-quality mRNA-seq was obtained from 76 patients (n=33 LS, n=28 idiopathic, and n=15 traumatic USD). A subset of tissues was also profiled by microRNA PCR (n=21) to evaluate for associations with LS-related genes. LS-associated genes and miRNAs were identified using linear modeling. Pathways and cell types were identified using GSVA. Potential regulatory relationships were identified based on significant miRNA-gene expression anti-correlation and if the gene was a known target.
RESULTS: Analysis revealed 1322 genes to be differentially expressed at FDR<0.01 (677 upregulated and 645 downregulated) in LS versus non-LS USD (Figure 1). LS patients exhibited significant downregulation of estrogen and steroid pathways and upregulation of inflammatory pathways. miRNAs differentially expressed between LS and non-LS USD (n=33, FDR<0.15) were potential gene regulators associated with these signaling pathways. Genes implicated in epithelial and mesenchymal tissue remodeling were also differentially expressed in LS versus non-LS patients (Figure 2).
CONCLUSIONS: Distinct gene expression differences were identified in LS versus non-LS USD patients and were largely implicated in immune, hormonal and fibrotic processes. Further insights could lead to biomarker or therapeutic targets for future LS diagnosis, treatment and prevention.
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