Aggarwal Amit, Guo Dong Li, Hoshida Yujin, Yuen Siu Tsan, Chu Kent-Man, So Samuel, Boussioutas Alex, Chen Xin, Bowtell David, Aburatani Hiroyuki, Leung Suet Yi, Tan Patrick
Cellular and Molecular Research, National Cancer Centre of Singapore, Singapore.
Cancer Res. 2006 Jan 1;66(1):232-41. doi: 10.1158/0008-5472.CAN-05-2232.
Gastric cancer is a leading cause of global cancer mortality, but comparatively little is known about the cellular pathways regulating different aspects of the gastric cancer phenotype. To achieve a better understanding of gastric cancer at the levels of systems topology, functional modules, and constituent genes, we assembled and systematically analyzed a consensus gene coexpression meta-network of gastric cancer incorporating >300 tissue samples from four independent patient populations (the "gastrome"). We find that the gastrome exhibits a hierarchical scale-free architecture, with an internal structure comprising multiple deeply embedded modules associated with diverse cellular functions. Individual modules display distinct subtopologies, with some (cellular proliferation) being integrated within the primary network, and others (ribosomal biosynthesis) being relatively isolated. One module associated with intestinal differentiation exhibited a remarkably high degree of autonomy, raising the possibility that its specific topological features may contribute towards the frequent occurrence of intestinal metaplasia in gastric cancer. At the single-gene level, we discovered a novel conserved interaction between the PLA2G2A prognostic marker and the EphB2 receptor, and used tissue microarrays to validate the PLA2G2A/EphB2 association. Finally, because EphB2 is a known target of the Wnt signaling pathway, we tested and provide evidence that the Wnt pathway may also similarly regulate PLA2G2A. Many of these findings were not discernible by studying the single patient populations in isolation. Thus, besides enhancing our knowledge of gastric cancer, our results show the broad utility of applying meta-analytic approaches to genome-wide data for the purposes of biological discovery.
胃癌是全球癌症死亡的主要原因，但对于调控胃癌表型不同方面的细胞途径，我们了解得相对较少。为了在系统拓扑结构、功能模块和组成基因层面更好地理解胃癌，我们整合并系统分析了一个胃癌的一致性基因共表达元网络，该网络纳入了来自四个独立患者群体的300多个组织样本（“胃基因组”）。我们发现胃基因组呈现出一种分层的无标度架构，其内部结构包含多个与不同细胞功能相关的深度嵌入模块。各个模块显示出不同的子拓扑结构，一些（细胞增殖）整合在主网络中，而其他一些（核糖体生物合成）则相对孤立。一个与肠化生相关的模块表现出高度的自主性，这增加了其特定拓扑特征可能导致胃癌中肠化生频繁发生的可能性。在单基因水平上，我们发现了磷脂酶A2G2A（PLA2G2A）预后标志物与EphB2受体之间一种新的保守相互作用，并使用组织微阵列验证了PLA2G2A/EphB2的关联。最后，由于EphB2是已知的Wnt信号通路靶点，我们进行了测试并提供证据表明Wnt通路可能同样调控PLA2G2A。单独研究单个患者群体时，许多这些发现并不明显。因此，除了增进我们对胃癌的了解外，我们的结果还表明，为了生物学发现的目的，将元分析方法应用于全基因组数据具有广泛的实用性。
