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.

中文翻译：

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基因表达谱定义了具有不同结果和可追溯至原发肿瘤的形态的前列腺癌骨转移的分子亚型。

骨转移是前列腺癌（PC）的致命终末期，但对骨转移的生物学了解甚少。因此，本研究的总体目标是探索对治疗潜在重要的PC骨转移的分子变异性。具体而言，分析了未经治疗的患者（n = 12）和接受雄激素剥夺治疗（ADT，n = 60）的患者的骨转移的全基因组表达谱，这些结果与患者的预后以及转移和配对原发肿瘤的形态特征相关。主成分分析和无监督分类用于基于mRNA谱图识别样品簇。通过基因集富集分析对聚类进行表征，并使用单变量和多变量统计将其与组织学和临床参数相关。通过免疫组织化学分析选择的蛋白质在转移和匹配的原发肿瘤中（n = 52）和在一个独立队列的经尿道切除前列腺（TUR-P）组织中（n = 59）。确定了三种以基因表达方式，形态和临床行为差异为特征的骨转移分子亚型（MetA-C）。MetA（71％的病例）显示出雄激素受体调节基因的表达增加，包括前列腺特异性抗原（PSA）和腺体结构，表明腔细胞表型。MetB（17％）显示与细胞周期活性和DNA损伤相关的表达谱，以及明显的细胞异型性。MetC（12％）表现出丰富的基质-上皮细胞相互作用。MetB患者的血清PSA水平最低，ADT后的预后最差。骨转移，配对的原发肿瘤和TUR-P样品中PSA和Ki67免疫反应性（增殖）的组合分析能够区分MetA类（高PSA，低Ki67）和MetB类（低PSA，高Ki67）肿瘤，证明他们不同的预后。总之，根据基因表达谱将PC患者的骨转移分为具有不同形态，生物学和临床结局的分子亚型。这些发现值得进一步探索，以改善转移性PC的治疗。根据基因表达谱将PC患者的骨转移分为具有不同形态，生物学和临床结局的分子亚型。这些发现值得进一步探索，以改善转移性PC的治疗。根据基因表达谱将PC患者的骨转移分为具有不同形态，生物学和临床结局的分子亚型。这些发现值得进一步探索，以改善转移性PC的治疗。