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

Middleton, Lance W.; Shen, Zhewei; Varma, Sushama; Pollack, Anna S.; Gong, Xue; Zhu, Shirley; Zhu, Chunfang; Foley, Joseph W.; Vennam, Sujay; Sweeney, Robert T.; Tu, Karen; Biscocho, Jewison; Eminaga, Okyaz; Nolley, Rosalie; Tibshirani, Robert; Brooks, James D.; West, Robert B.; Pollack, Jonathan R.

doi:10.1172/jci.insight.129749

Cited by 32 publications

(45 citation statements)

References 67 publications

(65 reference statements)

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“…6). We next validated this BPH transcriptional signature using two independent study cohorts 18,30 , and again found reliable clustering of BPH samples ( Fig. 2c, d) with similar upregulation of BMP5 identified (Supplementary Table 9).…”

Section: And 4 Supplementarymentioning

confidence: 57%

“…Histologically, BPH is characterized as the overgrowth of stromal and epithelial cells, and it occurs in the transition zone of the prostate 1 . Currently, many BPH studies have focused on risk factors of BPH [11][12][13] , while the underlying molecular features of BPH remain understudied 3,9,[14][15][16] and molecular data is relatively scarce 17,18 . Moreover, BPH has been described as the most common benign tumor in men, and is commonly referred to as an adenoma, but unlike many malignant 19 and benign neoplasms [20][21][22] , it is unknown whether BPH is a neoplastic process 3,7,[15][16][17] .…”

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confidence: 99%

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Integrative multiplatform molecular profiling of benign prostatic hyperplasia identifies distinct subtypes

Shoag

Poliak

et al. 2020

Nat Commun

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Benign prostatic hyperplasia (BPH), a nonmalignant enlargement of the prostate, is among the most common diseases affecting aging men, but the underlying molecular features remain poorly understood, and therapeutic options are limited. Here we employ a comprehensive molecular investigation of BPH, including genomic, transcriptomic and epigenetic profiling. We find no evidence of neoplastic features in BPH: no evidence of driver genomic alterations, including low coding mutation rates, mutational signatures consistent with aging tissues, minimal copy number alterations, and no genomic rearrangements. At the epigenetic level, global hypermethylation is the dominant process. Integrating transcriptional and methylation signatures identifies two BPH subgroups with distinct clinical features and signaling pathways, validated in two independent cohorts. Finally, mTOR inhibitors emerge as a potential subtype-specific therapeutic option, and men exposed to mTOR inhibitors show a significant decrease in prostate size. We conclude that BPH consists of distinct molecular subgroups, with potential for subtype-specific precision therapy.

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Section: And 4 Supplementarymentioning

confidence: 57%

mentioning

confidence: 99%

Integrative multiplatform molecular profiling of benign prostatic hyperplasia identifies distinct subtypes

Shoag

Poliak

et al. 2020

Nat Commun

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“…When compared to control samples from the normal peripheral zone, this transcriptional signature was BPH specific, and not specific to transition zone tissue ( Figure S2). We next validated this BPH transcriptional signature using two independent study cohorts 21,32 , and again found reliable clustering of BPH samples ( Figures 2C and 2D) with similar upregulation of BMP5 identified (Table S6).…”

Section: Resultsmentioning

confidence: 58%

“…We therefore performed integrative analysis using transcriptional and methylation profiling, and identified two distinct BPH subtypes ( Figure 3A and Tables S6-7), supporting robust biologically distinct subgroups across different data types. To validate distinct subtypes in BPH, we tested our signature via k-means clustering in two independent cohorts 20,21 , and identified nearly identical subgroups (Figures 3C, 3E and Table S8), further supporting the robustness of these subgroups across data types and sources. We then examined the molecular and clinical features of these two groups.…”

Section: Resultsmentioning

confidence: 66%

“…Histologically, BPH is characterized as the overgrowth of stromal and epithelial cells, and it occurs in the transitional zone of prostate 1 . Currently, many BPH studies have focused on risk factors of BPH 12,13,14,15 , while the underlying molecular features of BPH remain understudied 3,9,16,17,18,19 and molecular data is relatively scarce 20,21 . Moreover, BPH has been described as "the most common benign tumor in men", and is commonly referred to as an adenoma, but unlike many malignant 22,23 and benign neoplasms 24,25,26 , it is unknown whether BPH is a neoplastic process 3,7,18,19,20 .…”

Section: Introductionmentioning

confidence: 99%

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Integrative genomic, transcriptomic, and epigenomic analyses of benign prostatic hyperplasia reveal new options for therapy

Shoag

Poliak

et al. 2019

Preprint

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Benign prostatic hyperplasia (BPH), a nonmalignant enlargement of the prostate, is one of the most common diseases affecting aging men, but the underlying molecular features of BPH remain poorly understood, and therapeutic options are limited. Here we employed a comprehensive molecular investigation of BPH, including genomic, transcriptomic and epigenetic profiling of 18 BPH cases. At the molecular level, we found no evidence of neoplastic features in BPH: no evidence of driver genomic alterations, including low coding mutation rates, mutational signatures consistent with aging tissues, minimal copy number alterations, and no genomic rearrangements.Similarly at the epigenetic level, we found global hypermethylation was the dominant process (unlike most neoplastic processes). By integrating transcriptional and methylation signatures, we identified two BPH subgroups with distinct clinical features and associated signaling pathways, which were validated in two independent cohorts.Finally, our analyses nominated mTOR inhibitors as a potential subtype-specific therapeutic option. Supporting this, a cohort of men exposed to mTOR inhibitors showed a significant decrease in prostate size. Our results demonstrate that BPH consists of distinct molecular subgroups, with potential for subtype-specific precision therapy via mTOR inhibition.

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Upregulated bone morphogenetic protein 5 enhances proliferation and epithelial–mesenchymal transition process in benign prostatic hyperplasia via BMP/Smad signaling pathway

Liu

et al. 2021

The Prostate

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Background: Benign prostatic hyperplasia (BPH) is one of the most common illnesses in aging men. Recent studies found that bone morphogenetic protein 5 (BMP5) is upregulated in BPH tissues, however, the role of BMP5 in the development of BPH has not been examined. The current study aims to elucidate the potential roles of BMP5 and related signaling pathways in BPH.Methods: Human prostate cell lines (BPH-1, WPMY-1) and human/rat hyperplastic prostate tissues were utilized. Western blot, quantitative real-time polymerase chain reaction, immunofluorescent staining, and immunohistochemical staining were performed. BMP5-silenced and -overexpressed cell models were generated and then cell cycle progression, apoptosis, and proliferation were determined. The epithelial-mesenchymal transition (EMT) was also quantitated. And rescue experiments by BMP/Smad signaling pathway agonist or antagonist were accomplished.Moreover, BPH-related tissue microarray analysis was performed and associations between clinical parameters and expression of BMP5 were analyzed.Results: Our study demonstrated that BMP5 was upregulated in human and rat hyperplastic tissues and localized both in the epithelial and stromal compartments of the prostate tissues. E-cadherin was downregulated in hyperplastic tissues, while N-cadherin and vimentin were upregulated. Overexpression of BMP5 enhanced cell proliferation and the EMT process via phosphorylation of Smad1/5/8, while knockdown of BMP5 induced cell cycle arrest at G0/G1 phase and blocked the EMT process. Moreover, a BMP/Smad signaling pathway agonist and antagonist reversed the effects of BMP5 silencing and overexpression, respectively. In addition, BMP5

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

Cited by 32 publications

References 67 publications

Integrative multiplatform molecular profiling of benign prostatic hyperplasia identifies distinct subtypes

Integrative multiplatform molecular profiling of benign prostatic hyperplasia identifies distinct subtypes

Integrative genomic, transcriptomic, and epigenomic analyses of benign prostatic hyperplasia reveal new options for therapy

Upregulated bone morphogenetic protein 5 enhances proliferation and epithelial–mesenchymal transition process in benign prostatic hyperplasia via BMP/Smad signaling pathway

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