Commentary on "Integrative multiplatform molecular profiling of benign prostatic hyperplasia identifies distinct subtypes".

Abstract

Benign prostatic hyperplasia (BPH) occurs commonly in older males, with its prevalence increasing linearly with age, reaching approximately 50% and 80% in males aged 60 and 90 years, respectively.[1] Histologically, BPH is characterized by smooth muscle and epithelial cell proliferation within the prostatic transitional zone. Subsequent anatomical compression of the urethra causes increased bladder outlet resistance and detrusor muscle irritability, usually resulting in lower urinary tract symptoms (LUTS), which can be bothersome and make patients seek medical care. Current treatments for LUTS associated with BPH consist primarily of watchful waiting, medical therapy, and surgical intervention. Although there has been a recent surge in highly effective minimally invasive surgical options, such as Rezum or Urolift, medical therapy with alpha-adrenergic blockers (ABs) and/or 5-alpha-reductase inhibitors (5-ARIs) is still preferred to surgical intervention in older adults. Among them, ABs quickly and effectively relieve LUTS by reducing smooth muscle tone within the prostate and bladder neck. However, only 5-ARIs reduce the prostate volume and the risk of BPH progression by decreasing dihydrotestosterone levels and blocking androgen receptor signaling in the prostate. Long-term clinical data showed that 5-ARIs could effectively reduce prostate volume by 20% in 4 to 6 months and decrease the demand for surgery by 69%.[2] Unfortunately, at least 25% to 30% of patients are unresponsive to 5-ARIs, and 5% to 7% develop worsening symptoms, ultimately requiring surgical treatment.[2] Notably, 20% to 30% of BPH patients treated with 5-ARIs experience serious side effects, such as sexual dysfunction, reduced libido, infertility, mood disorders, and cardiovascular morbidity.[3,4] However, since there are no specific biomarkers to distinguish BPH patients who are sensitive to 5-ARIs, physicians passively administer standardized treatment recommended in the guidelines to these patients in current clinical practice. Consequently, some BPH patients have to bear long-term ineffective treatments and related side effects and miss other effective therapies. This impairs their quality of life, increases their economic burden, and brings about tremendous waste of healthcare resources. Clearly, there is a lack of a deeper understanding of BPH and an inability to provide rational interventional strategies, which could be attributed to a deficiency in awareness of the patient's actual disease status. We have read an article by Liu et al[5] and were very impressed. They performed a comprehensive, multi-level molecular investigation of BPH to enrich the transcriptional landscape of BPH. Interestingly, unlike previous studies, they focused on molecular profiling differences within the BPH group and sought to distinguish specific subgroups from clinical features and molecular markers. Their study highlights that BPH is a heterogeneous disease and urges the importance of precision medicine in BPH management. Liu et al found that BPH was highly associated with underlying mutational processes related to aging using whole-genome sequencing, whole-exome sequencing, and single-nucleotide polymorphism arrays in 18 BPH samples and matched controls. This was consistent with the higher BPH prevalence in older patients. Moreover, unlike neoplastic diseases, BPH harbors far fewer somatic coding mutations (SNVs) and no recurrent SNVs, suggesting an absence of driver alterations in the development of BPH. In contrast to primary prostate cancer, BPH displayed fewer copy number alterations, a lower altered genome fraction, and no genomic rearrangements. Furthermore, they investigated the DNA methylation landscapes in the BPH samples and five controls from normal transition zone tissue. Unlike that in primary prostate cancer, the DNA methylation landscape in BPH was characterized by hypermethylation. Based on the above evidence, Lui et al demonstrated that BPH might be a consequence of aging rather than a neoplastic process. Next, Liu et al identified two BPH subgroups using principal component analysis based on transcriptional and methylation profiling of the BPH samples. The reliability of these two subgroups was strongly confirmed by testing their signature in two independent cohorts. They further examined the molecular and clinical features of these subgroups, labeling one subgroup, characterized by upregulated stromal signaling, as BPH-A, and the other, associated with obesity (body mass index > 30) and hypertension, as BPH-B. More interestingly, connectivity map analysis, a database analyzing transcriptional expression data to reveal relationships between diseases, genes, and therapeutics, was used to identify potential subtype-specific therapeutic options for these two BPH subgroups. Hence, they concluded that 50% of the nominated compounds in the BPH-A subgroup were related to the inhibition of the mammalian target of mTOR signaling, indicating that mTOR inhibitors might serve as a promising therapeutic option for the BPH-A group. Furthermore, they collected the computed tomography images of 47 patients who took mTOR inhibitors for transplant or non-prostate malignancy therapies and 12 patients with nephrolithiasis as controls. Then, they compared prostate sizes between the groups to validate their findings. After 6 months of mTOR inhibitors treatment, 17 of the 47 patients showed an average of 12.5% reduction in prostate size compared with their prostate sizes at the onset of therapy. In contrast, none of the patients in the control group showed a significant decrease in prostate size, consistent with the previous finding. However, this study may have the following limitations. It is a pity that this study failed to capture the consistent pathological changes with activated stromal signaling in prostate tissues. In clinical practice, we observed that advanced BPH is usually characterized by multiple macroscopic nodules on gross examination. However, these nodules showed diversified histopathological manifestations in different BPH tissues under a microscope. In most BPH tissues, the nodules appeared to be a mixture of glandular epithelium and stroma, while in some tissues, the main component was hyperplasia of the glandular epithelium or stroma. It is of great possibility that these nodules with different cellular components might have originated from different pathophysiological processes, and in future studies we need to ascertain the precise molecular changes in different pathomorphological BPH nodules. This study, considered in the light of similar findings from the literature, conveys the message that BPH is a heterogeneous disease, and that treating BPH patients based exclusively on prostate volume and similar clinical symptoms, as appears to be the vogue in current clinical practice, is not the best option. Currently, most research focuses on exploring relevant pathways in BPH occurrence and development to apply targeted therapies. However, these studies are still limited to comparing normal prostatic tissues with BPH tissues, ignoring the underlying differences in the BPH group, which inevitably leads to the limited efficacy of a new drug. Therefore, further is needed to: (1) design more experiments that decipher the clinical and molecular features and histopathological changes underlying the various BPH subtypes, (2) formulate protocols based on a combination of clinical characteristics, imaging features, pathological examination, and new molecular markers to identify BPH subtypes, and (3) develop therapeutic drugs targeting specific BPH subtypes to advance precise medicine. Funding This work is supported by the National Natural Science Foundation of China (No. 82170783) at Beijing Shijitan Hospital, Capital Medical University. Conflicts of interest None.