Genomic analysis of benign prostatic hyperplasia implicates cellular relandscaping in disease pathogenesis

• DOI: 10.1172/jci.insight.129749
• Publication Date: 2019-05-16T16:00:59Z
• Authors: Lance W. Middleton; Zhewei Shen; Sushama Varma; Anna S. Pollack; Xue Gong; Shirley Zhu; Chunfang Zhu; Joseph W. Foley; Sujay Vennam; Robert T. Sweeney; Karen Tu; Jewison Biscocho; Okyaz Eminaga; Rosalie Nolley; Robert Tibshirani; James D. Brooks; Robert B. West; Jonathan R. Pollack
• Keywords: Male; 0303 health sciences; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Bone Morphogenetic Protein 5; Severity of Illness Index; 03 medical and health sciences; Neuroendocrine Cells; Receptors, Estrogen; Humans; Exome; Genetic Predisposition to Disease; Myofibroblasts; Transcriptome

Benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptoms in men. Current treatments target prostate physiology rather than BPH pathophysiology and are only partially effective. Here, we applied next-generation sequencing to gain new insight into BPH. By RNAseq, we uncovered transcriptional heterogeneity among BPH cases, where a 65-gene BPH stromal signature correlated with symptom severity. Stromal signaling molecules BMP5 and CXCL13 were enriched in BPH while estrogen regulated pathways were depleted. Notably, BMP5 addition to cultured prostatic myofibroblasts altered their expression profile towards a BPH profile that included the BPH stromal signature. RNAseq also suggested an altered cellular milieu in BPH, which we verified by immunohistochemistry and single-cell RNAseq. In particular, BPH tissues exhibited enrichment of myofibroblast subsets, whilst depletion of neuroendocrine cells and an estrogen receptor (ESR1)-positive fibroblast cell type residing near epithelium. By whole-exome sequencing, we uncovered somatic single-nucleotide variants (SNVs) in BPH, of uncertain pathogenic significance but indicative of clonal cell expansions. Thus, genomic characterization of BPH has identified a clinically-relevant stromal signature and new candidate disease pathways (including a likely role for BMP5 signaling), and reveals BPH to be not merely a hyperplasia, but rather a fundamental re-landscaping of cell types.