Burdelski Christoph, Matuszewska Aleksandra, Kluth Martina, Koop Christina, Grupp Katharina, Steurer Stefan, Wittmer Corinna, Minner Sarah, Tsourlakis Maria Christina, Sauter Guido, Schlomm Thorsten, Simon Ronald
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
Microarrays (Basel). 2014 Apr 17;3(2):137-58. doi: 10.3390/microarrays3020137.
Molecular prognostic markers are urgently needed in order to improve therapy decisions in prostate cancer. To better understand the requirements for biomarker studies, we re-analyzed prostate cancer tissue microarray immunohistochemistry (IHC) data from 39 prognosis markers in subsets of 50 - >10,000 tumors. We found a strong association between the "prognostic power" of individual markers and the number of tissues that should be minimally included in such studies. The prognostic relevance of more than 90% of the 39 IHC markers could be detected if ≥6400 tissue samples were analyzed. Studying markers of tissue quality, including immunohistochemistry of ets-related gene (ERG) and vimentin, and fluorescence in-situ hybridization analysis of human epidermal growth factor receptor 2 (HER2), we found that 18% of tissues in our tissue microarray (TMA) showed signs of reduced tissue preservation and limited immunoreactivity. Comparing the results of Kaplan-Meier survival analyses or associations to ERG immunohistochemistry in subsets of tumors with and without exclusion of these defective tissues did not reveal statistically relevant differences. In summary, our study demonstrates that TMA-based marker validation studies using biochemical recurrence as an endpoint require at least 6400 individual tissue samples for establishing statistically relevant associations between the expression of molecular markers and patient outcome if weak to moderate prognosticators should also be reliably identified.
为了改善前列腺癌的治疗决策，迫切需要分子预后标志物。为了更好地理解生物标志物研究的要求，我们重新分析了来自50 - >10,000例肿瘤亚组中39种预后标志物的前列腺癌组织微阵列免疫组织化学（IHC）数据。我们发现个体标志物的“预后能力”与此类研究中应最少纳入的组织数量之间存在密切关联。如果分析≥6400个组织样本，则可以检测出39种IHC标志物中90%以上的预后相关性。通过研究组织质量标志物，包括ets相关基因（ERG）和波形蛋白的免疫组织化学，以及人表皮生长因子受体2（HER2）的荧光原位杂交分析，我们发现组织微阵列（TMA）中18%的组织显示出组织保存减少和免疫反应性受限的迹象。在有和没有排除这些有缺陷组织的肿瘤亚组中，比较Kaplan-Meier生存分析结果或与ERG免疫组织化学的关联，未发现统计学上的显著差异。总之，我们的研究表明，如果还应可靠地识别弱至中度预后指标，那么以生化复发为终点的基于TMA的标志物验证研究需要至少6400个个体组织样本，以建立分子标志物表达与患者预后之间的统计学显著关联。
