Integrative multiplatform molecular profiling of benign prostatic hyperplasia identifies distinct subtypes

Abstract

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.

TNF Blockade Reduces Prostatic Hyperplasia and Inflammation while Limiting BPH Diagnosis in Patients with Autoimmune Disease

“…Since BPH patients have one or more of a variety of histological features, including stromal nodules, glandular nodules, and/or fibrosis, this disease is more likely a combination of conditions ( 51 ). Recent molecular profiling studies have provided a basis for at least two BPH subtypes ( 12 ). As in prostate development, it has long been clear that paracrine interactions between stromal and epithelial tissues are important in BPH ( 41 ).…”

“…The only definitive risk factors for developing BPH are male sex and increasing age, but BPH has been linked to decreased systemic androgen:estrogen ratios, obesity, type 2 diabetes, metabolic syndrome, and inflammation ( 3–9 ). There is a paucity of studies investigating possible genetic determinants of BPH, although, more recently, there has been greater interest in this area ( 10–12 ). The medical therapeutic options used for men with LUTS related to BPH are limited (e.g.…”

Management of benign prostate hyperplasia (BPH) by combinatorial approach using alpha-1-adrenergic antagonists and 5-alpha-reductase inhibitors

“…While BPH-A subtype is characterised by stromal-tissue-like features, BPH-B subtype has specific dysregulations involving metabolic pathways in the patients with obesity (BMI>30) and hypertension. Abnormal metabolism is also reported in BPH-A subgroup when compared to age-matched control samples (Liu et al, 2020;Tomlins et al, 2007). BPH-A subtype has been correlated with mTOR inhibition in 50% of the nominated sample of BPH-A subgroup and has been investigated as a potential therapeutic option for BPH patients (Fingar et al, 2002;Tumaneng et al, 2012).…”

“…According to the recently published molecular profiling, two biologically distinct BPH subtypes have been identified, which were referred to as BPH-A subgroup and BPH-B subgroup (Liu et al, 2020). While BPH-A subtype is characterised by stromal-tissue-like features, BPH-B subtype has specific dysregulations involving metabolic pathways in the patients with obesity (BMI>30) and hypertension.…”

KRAS, BRAF, PIK3CA mutation frequency of radical prostatectomy samples and review of the literature

“…In fact, in a recent NGS study, no evidence of driver genomic alterations was found in BPH cases, inconsistent with a neoplastic process. Even they observed multiple signatures related to the inactivation of KRAS signaling [117].…”