Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor

Abstract

Bone metastasis is the lethal end‐stage of prostate cancer (PC), but the biology of bone metastases is poorly understood. The overall aim of this study was therefore to explore molecular variability in PC bone metastases of potential importance for therapy. Specifically, genome‐wide expression profiles of bone metastases from untreated patients ( n = 12) and patients treated with androgen‐deprivation therapy (ADT, n = 60) were analyzed in relation to patient outcome and to morphological characteristics in metastases and paired primary tumors. Principal component analysis and unsupervised classification were used to identify sample clusters based on mRNA profiles. Clusters were characterized by gene set enrichment analysis and related to histological and clinical parameters using univariate and multivariate statistics. Selected proteins were analyzed by immunohistochemistry in metastases and matched primary tumors ( n = 52) and in transurethral resected prostate (TUR‐P) tissue of a separate cohort ( n = 59). Three molecular subtypes of bone metastases (MetA‐C) characterized by differences in gene expression pattern, morphology, and clinical behavior were identified. MetA (71% of the cases) showed increased expression of androgen receptor‐regulated genes, including prostate‐specific antigen (PSA), and glandular structures indicating a luminal cell phenotype. MetB (17%) showed expression profiles related to cell cycle activity and DNA damage, and a pronounced cellular atypia. MetC (12%) exhibited enriched stroma–epithelial cell interactions. MetB patients had the lowest serum PSA levels and the poorest prognosis after ADT. Combined analysis of PSA and Ki67 immunoreactivity (proliferation) in bone metastases, paired primary tumors, and TUR‐P samples was able to differentiate MetA‐like (high PSA, low Ki67) from MetB‐like (low PSA, high Ki67) tumors and demonstrate their different prognosis. In conclusion, bone metastases from PC patients are separated based on gene expression profiles into molecular subtypes with different morphology, biology, and clinical outcome. These findings deserve further exploration with the purpose of improving treatment of metastatic PC.

A novel DNA methylation signature is associated with androgen receptor activity and patient prognosis in bone metastatic prostate cancer

“…Samples of bone metastases were obtained from a series of fresh-frozen biopsies collected from 70 patients with PC operated for metastatic spinal cord compression at Umeå University Hospital (2003–2013). The patient series have been previously described [ 7 , 9 , 12 ] and clinical characteristics of patients included in the current study are summarized in Table 1 . The study also included 12 separate patients with localized PC who were treated with radical prostatectomy at Umeå University Hospital, between 2008 and 2009; mean age for these men was 60 years (range 48–68 years) and mean serum level of prostate specific antigen (PSA) was 11 ng/ml (range 3.5–26 ng/ml).…”

“…By exploring the gene expression in clinical samples of PC bone metastases, we have identified transcriptomic as well as proteomic profiles of suggested clinical relevance [ 7 – 12 ]. Specifically, we have identified three molecular subtypes of bone metastases, termed MetA–C, based on the diverged expression of genes related to AR activity, cell cycle activity, and stroma response [ 12 ]. The MetA subtype shows high AR activity in comparison to MetB and C, while MetB shows higher cell cycle activity than the other subtypes.…”

“…Accordingly, MetA patients have the best prognosis after ADT, while MetB patients have by far the worst prognosis. Interestingly, the MetA–C subtypes could be intrinsic, as selected features of MetB (low AR activity and high proliferation) were traceable back to the corresponding primary tumors [ 12 ]. In line with this, PC subtypes with characteristics similar to the MetA–C subtypes have been identified by transcriptomic analysis of primary prostate tumors [ 13 , 14 ].…”

Personal Medicine and Bone Metastases: Biomarkers, Micro-RNAs and Bone Metastases

“…Studies performing genome-wide expression studies (GWAS) within prostate cancer bone metastases from patients who were either untreated or subjected to androgen-deprivation therapy (ADT) have identified three distinct molecular subtypes within bone lesions [ 37 ]. These three subtypes termed MetA-C display unique gene expression profiles.…”

“…The other molecular subtypes observed classified as MetB and MetC were responsible for 17% and 12% of cases, respectively. MetB bone metastases have alterations in genes associated with DNA damage repair and cell cycle regulation, whilst MetC metastases have enrichment for genes involved in stromal-epithelial cell interactions [ 37 ]. These genetic profiles within bone metastases were observed to correlate with different therapeutic outcomes, in particular, MetB bone metastases had the lowest levels of serum PSA as well as the poorest outcomes following ADT [ 37 ].…”