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.

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.