Department of Pathology, Josephine Nefkens Institute, Erasmus University Medical Centre, Rotterdam, The Netherlands.
Eur Urol. 2013 Dec;64(6):941-50. doi: 10.1016/j.eururo.2013.02.039. Epub 2013 Mar 7.
The molecular basis of the clinical heterogeneity of prostate cancer (PCa) is not well understood.
The purpose of our study was to identify and characterize genes in a clinically relevant gene expression signature in a subgroup of primary PCa positive for transmembrane protease, serine 2 (TMPRSS2)-v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG).
DESIGN, SETTING, AND PARTICIPANTS: We studied gene expression profiles by unsupervised hierarchical clustering in 48 primary PCas from patients with a long clinical follow-up. Results were correlated with clinical outcome and validated in an independent patient cohort. Selected genes from a defined classifier were tested in vitro for biologic properties.
Initial treatment of primary tumors was radical prostatectomy.
Associations between clinical and histopathologic variables were evaluated by the Pearson χ(2) test, Mann-Whitney U test, or Kruskal-Wallis test, where appropriate. The log-rank test or Breslow method was used for statistical analysis of Kaplan-Meier survival curves.
Most tumors that overexpressed ERG clustered separately from other primary PCas. No differences in any clinical end points between ERG-positive and ERG-negative cancers were detected. Importantly, within the ERG-positive samples, two subgroups were identified, which differed significantly in prostate-specific antigen recurrence-free survival, and cancer-specific and overall survival. From our findings, we defined a gene expression classifier of 36 genes. In a second, completely independent tumor set, the classifier also distinguished ERG-positive subgroups with different clinical outcome. In both patient cohorts, the classifier was not predictive in ERG-negative tumors. Biologic processes regulated by genes in the classifier included cell adhesion and bone remodeling. Tumor growth factor-β signaling was indicated as the main differing signaling pathway between the two ERG subgroups. In vitro biologic assays of two selected genes from the classifier (inhibin, beta A [INHBA] and cadherin 11, type 2, OB-cadherin (osteoblast) [CDH11]) supported a functional role in PCa progression. Possible multifocality and limited number of PCa samples can be limitations of the study.
The classifier identified can contribute to prediction of tumor progression in ERG-positive primary prostate tumors and might be instrumental in therapy decisions.
前列腺癌（PCa）临床异质性的分子基础尚不清楚。
我们的研究目的是鉴定和描述一组临床相关基因表达谱中的基因，该基因在膜蛋白酶，丝氨酸 2（TMPRSS2）-v-ets 红细胞生成病毒 E26 癌基因同源物（禽）（ERG）阳性的原发性 PCa 亚组中。
设计、设置和参与者：我们通过无监督层次聚类研究了 48 例具有长期临床随访的原发性 PCa 的基因表达谱。结果与临床结果相关，并在独立的患者队列中得到验证。从定义的分类器中选择基因，并在体外测试其生物学特性。
初始治疗为根治性前列腺切除术。
采用 Pearson χ(2)检验、Mann-Whitney U 检验或 Kruskal-Wallis 检验评估临床和组织病理学变量之间的相关性。对数秩检验或 Breslow 法用于 Kaplan-Meier 生存曲线的统计学分析。
大多数过度表达 ERG 的肿瘤与其他原发性 PCa 分离。在 ERG 阳性和 ERG 阴性癌症之间未检测到任何临床终点的差异。重要的是，在 ERG 阳性样本中，鉴定出两个亚组，在前列腺特异性抗原无复发生存、癌症特异性和总生存方面存在显著差异。根据我们的发现，我们定义了一个由 36 个基因组成的基因表达分类器。在第二个完全独立的肿瘤集，分类器也区分了具有不同临床结局的 ERG 阳性亚组。在两个患者队列中，分类器在 ERG 阴性肿瘤中均无预测性。分类器中基因调节的生物学过程包括细胞粘附和骨重塑。肿瘤生长因子-β信号被认为是两个 ERG 亚组之间主要的差异信号通路。体外生物学检测两个分类器中选定基因（抑制素，β A [INHBA]和钙粘蛋白 11，2 型，OB-钙粘蛋白（成骨细胞）[CDH11]）的实验表明其在前列腺癌进展中具有功能作用。可能存在多灶性和有限数量的 PCa 样本可能是该研究的局限性。
鉴定的分类器可有助于预测 ERG 阳性原发性前列腺肿瘤的肿瘤进展，并可能有助于治疗决策。
