Cross-species comparison of human and mouse intestinal polyps reveals conserved mechanisms in adenomatous polyposis coli (APC)-driven tumorigenesis
Cross-species comparison of human and mouse intestinal polyps reveals conserved mechanisms in adenomatous polyposis coli (APC)-driven tumorigenesis
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DOI：
10.2353/ajpath.2008.070851
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发表时间：
2008-05-01
影响因子：
6
通讯作者：
Fodde, Riccardo
中科院分区：
文献类型：
--
作者：
Gaspar, Claudia;Cardoso, Joana;Fodde, Riccardo
表达谱分析是用于人类癌症的全基因组分析的成熟工具。然而，这种方法的高灵敏度与众所周知的癌症的细胞和分子异质性相结合，往往导致极其复杂的表达特征，难以从功能上解释。大多数散发性结直肠癌是由腺瘤性结肠息肉病（APC）肿瘤抑制基因突变触发的，导致Wnt/β-连环蛋白信号通路的组成性激活和腺瘤的形成。尽管有这种共同的遗传基础，结直肠。癌症在其分化程度、生长速率和恶性潜能方面是非常异质的。在这里，我们应用了一个跨物种的比较表达谱的肠息肉来自遗传性结直肠癌患者携带APC种系突变和小鼠携带有针对性的失活突变的小鼠同源Apc。这种比较方法导致建立了166个基因的保守签名，这些基因在两个物种的腺瘤和正常肠粘膜之间差异表达。保守基因的功能分析揭示了细胞增殖的普遍增加和Wnt/β-连环蛋白信号通路的激活。此外，保守的签名能够解析携带APC种系突变的遗传性息肉病患者与MYH基因双等位基因失活的患者的表达谱，支持这种比较在区分具有不同遗传缺陷的患者中的有用性。
Expression profiling is a well established tool for the genome-wide analysis of human cancers. However, the high sensitivity of this approach combined with the well known cellular and molecular heterogeneity of cancer often result in extremely complex expression signatures that are difficult to interpret functionally. The majority of sporadic colorectal cancers are triggered by mutations in the adenomatous polyposis coli (APC) tumor suppressor gene, leading to the constitutive activation of the Wnt/beta-catenin signaling pathway and formation of adenomas. Despite this common genetic basis, colorectal. cancers are very heterogeneous in their degree of differentiation, growth rate, and malignancy potential. Here, we applied a cross-species comparison of expression profiles of intestinal polyps derived from hereditary colorectal cancer patients carryingAPC germline mutations and from mice carrying a targeted inactivating mutation in the mouse homologueApc. This comparative approach resulted in the establishment of a conserved signature of 166 genes that were differentially expressed between adenomas and normal intestinal mucosa in both species. Functional analyses of the conserved genes revealed a general increase in cell proliferation and the activation of the Wnt/beta-catenin signaling pathway. Moreover, the conserved signature was able to resolve expression profiles from hereditary polyposis patients carrying APC germline mutations from those with bi-allelic inactivation of the MYH gene, supporting the usefulness of such comparisons to discriminate among patients with distinct genetic defects.