López-Ríos Fernando, Chuai Shannon, Flores Raja, Shimizu Shigeki, Ohno Takatoshi, Wakahara Kazuhiko, Illei Peter B, Hussain Sanaa, Krug Lee, Zakowski Maureen F, Rusch Valerie, Olshen Adam B, Ladanyi Marc
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cancer Res. 2006 Mar 15;66(6):2970-9. doi: 10.1158/0008-5472.CAN-05-3907.
Most gene expression profiling studies of mesothelioma have been based on relatively small sample numbers, limiting their statistical power. We did Affymetrix U133A microarray analysis on 99 pleural mesotheliomas, in which multivariate analysis showed advanced-stage, sarcomatous histology and P16/CDKN2A homozygous deletion to be significant independent adverse prognostic factors. Comparison of the expression profiles of epithelioid versus sarcomatous mesotheliomas identified many genes significantly overexpressed among the former, including previously unrecognized ones, such as uroplakins and kallikrein 11, both confirmed by immunohistochemistry. Examination of the gene expression correlates of survival showed that more aggressive mesotheliomas expressed higher levels of Aurora kinases A and B and functionally related genes involved in mitosis and cell cycle control. Independent confirmation of the negative effect of Aurora kinase B was obtained by immunohistochemistry in a separate patient cohort. A role for Aurora kinases in the aggressive behavior of mesotheliomas is of potential clinical interest because of the recent development of small-molecule inhibitors. We then used our data to develop microarray-based predictors of 1 year survival; these achieved a maximal accuracy of 68% in cross-validation. However, this was inferior to prognostic prediction based on standard clinicopathologic variables and P16/CDNK2A status (accuracy, 73%), and adding the microarray model to the latter did not improve overall accuracy. Finally, we evaluated three recently published microarray-based outcome prediction models, but their accuracies ranged from 63% to 67%, consistently lower than reported. Gene expression profiling of mesotheliomas is an important discovery tool, but its power in clinical prognostication has been overestimated.
大多数间皮瘤的基因表达谱研究都是基于相对较少的样本数量，这限制了它们的统计效力。我们对99例胸膜间皮瘤进行了Affymetrix U133A微阵列分析，多变量分析显示晚期、肉瘤样组织学类型和P16/CDKN2A纯合缺失是显著的独立不良预后因素。对上皮样与肉瘤样间皮瘤的表达谱进行比较，发现前者中有许多基因显著过表达，包括以前未被识别的基因，如尿路上皮蛋白和激肽释放酶11，两者均经免疫组织化学证实。对与生存相关的基因表达进行检测，结果显示侵袭性更强的间皮瘤表达更高水平的极光激酶A和B以及参与有丝分裂和细胞周期调控的功能相关基因。在另一组患者中通过免疫组织化学独立证实了极光激酶B的负面影响。由于小分子抑制剂的最新进展，极光激酶在间皮瘤侵袭性行为中的作用具有潜在的临床意义。然后，我们利用我们的数据开发了基于微阵列的1年生存率预测指标；在交叉验证中，这些指标的最大准确率为68%。然而，这低于基于标准临床病理变量和P16/CDNK2A状态的预后预测（准确率73%），并且将微阵列模型添加到后者中并没有提高总体准确率。最后，我们评估了最近发表的三种基于微阵列的预后预测模型，但其准确率在63%至67%之间，始终低于报道的水平。间皮瘤的基因表达谱分析是一种重要的发现工具，但其在临床预后判断中的作用被高估了。
