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

被引：32

作者：

Middleton, Lance W. ^{[1
]}

Shen, Zhewei ^{[1
]}

Varma, Sushama ^{[1
]}

Pollack, Anna S. ^{[1
]}

Gong, Xue ^{[1
,2
]}

Zhu, Shirley ^{[1
]}

Zhu, Chunfang ^{[1
]}

Foley, Joseph W. ^{[1
]}

Vennam, Sujay ^{[1
]}

Sweeney, Robert T. ^{[1
]}

Tu, Karen ^{[1
]}

Biscocho, Jewison ^{[1
]}

Eminaga, Okyaz ^{[2
]}

Nolley, Rosalie ^{[2
]}

Tibshirani, Robert ^{[3
,4
]}

Brooks, James D. ^{[2
]}

West, Robert B. ^{[1
]}

Pollack, Jonathan R. ^{[1
]}

机构：

[1] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA

[2] Stanford Univ, Sch Med, Dept Urol, 300 Pasteur Dr,S287, Stanford, CA 94305 USA

[3] Stanford Univ, Sch Med, Dept Biomed Data Sci, Stanford, CA 94305 USA

[4] Stanford Univ, Sch Med, Dept Stat, Stanford, CA 94305 USA

来源：

JCI INSIGHT | 2019年 / 4卷 / 12期

关键词：

URINARY-TRACT SYMPTOMS; NEUROENDOCRINE CELLS; CLINICAL PROGRESSION; METABOLIC SYNDROME; DIFFERENTIAL GENE; STROMAL CELLS; GROWTH-FACTOR; PROLIFERATION; EXPRESSION; ANDROGEN;

D O I：

10.1172/jci.insight.129749

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 insight into BPH. By RNA-Seq, we uncovered transcriptional heterogeneity among BPH cases, where a 65-gene BPH stromal signature correlated with symptom severity. Stromal signaling molecules bone morphogenetic protein 5 (BMP5) and CXC chemokine ligand 13 (CXCL13) were enriched in BPH while estrogen-regulated pathways were depleted. Notably, BMP5's addition to cultured prostatic myofibroblasts altered their expression profile toward a BPH profile that included the BPH stromal signature. RNA-Seq also suggested an altered cellular milieu in BPH, which we verified by immunohistochemistry and single-cell RNA-Seq. In particular, BPH tissues exhibited enrichment of myofibroblast subsets but also depletion of neuroendocrine cells and an estrogen receptor-positive fibroblast cell type residing near the epithelium. By whole-exome sequencing, we uncovered somatic single-nucleotide variants 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 relandscaping of cell types.

引用

页数：14