Integrated bioinformatic and wet-lab approach to identify potential oncogenic networks in neuroblastoma: MSX1. Homo sapiens

mRNA profiles of thousands of human tumors are available, but methods to deduce oncogenic signaling networks from these data lag behind. It is especially challenging to identify main-regulatory routes, and to generalize conclusions obtained from experimental models. We designed the bioinformatic platform R2 (http://r2.amc.nl) in parallel with a wet-lab approach of neuroblastoma. Here we demonstrate how R2 facilitates an integrated analysis of our neuroblastoma data. Analysis of the MYCN pathway suggested important regulatory connections to the polyamine synthesis route, the Notch pathway and the BMP/TGFβ pathway. A network of genes emerged connecting major oncogenes in neuroblastoma. Genes in the network carried strong prognostic values and were essential for tumor cell survival. Overall design: Triplicate time course experiments of MSX1 induction, with 4 timepoints.

目前已有数千例人类肿瘤的信使核糖核酸（mRNA）表达谱数据，但从这类数据中推导致癌信号网络的方法仍相对滞后。准确识别核心调控通路，并将实验模型所得结论进行泛化推广，这一过程尤为充满挑战。我们同步开发了生物信息学平台R2（http://r2.amc.nl），并配套开展了神经母细胞瘤的湿实验研究。本研究展示了R2平台如何助力我们对神经母细胞瘤数据开展整合分析。针对MYCN通路的分析显示，其与多胺合成通路、Notch通路以及BMP/TGFβ通路存在重要的调控关联。由此构建出了一个连接神经母细胞瘤主要致癌基因的基因调控网络。该网络中的基因均具有显著的预后价值，且对肿瘤细胞存活至关重要。整体实验设计：针对MSX1基因诱导开展三次重复的时间序列实验，共设置4个时间节点。