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PNAS:鉴别出引发髓母细胞瘤的特殊致病基因

来源:生物谷 2013-11-01 00:38

2013年11月1日 讯 /生物谷BIOON/ --近日,来自昆士兰大学的研究者通过研究发现了一些可以驱动髓母细胞瘤形成的基因,髓母细胞瘤是在儿童中发现的一种常见的恶性脑瘤,相关研究刊登于国际杂志Proceedings of the National Academy of Sciences上。

研究者Wainwright说道,脑瘤是一种最为常见的引发儿童死亡的癌症,那些通过一定疗法生存下来的儿童也会经常经受神经、智力及肢体上的各种残疾。

本文中,来自美国、澳大利亚等处的研究者研究者表示,目前需要更为有效及低侵入性的方法来治疗髓母细胞瘤,并且改善儿童以及成人的健康状况。他们通过对85种肿瘤进行筛选后发现了这些引发脑瘤的基因。

髓母细胞瘤有四种亚型,每一种都有其独特的分子特性,文中研究者在所有髓母细胞瘤的亚型中鉴别出了其背后的遗传调控网络,研究者目前正在寻找是否存在现成的药物可以有效阻断这些驱动疾病发生的基因网络,当然这些现成的疗法也可以作为治疗髓母细胞瘤的可选方法。(生物谷Bioon.com)

Sleeping Beauty mutagenesis in a mouse medulloblastoma model defines networks that discriminate between human molecular subgroups

Laura A. Genovesia,1,2, Ching Ging Ngb,1, Melissa J. Davisa, Marc Remkec, Michael D. Taylorc, David J. Adamsd, Alistair G. Rustd, Jerrold M. Wardb, Kenneth H. Bane, Nancy A. Jenkinsb,f, Neal G. Copelandb,f,2, and Brandon J. Wainwrighta,2

The Sleeping Beauty (SB) transposon mutagenesis screen is a powerful tool to facilitate the discovery of cancer genes that drive tumorigenesis in mouse models. In this study, we sought to identify genes that functionally cooperate with sonic hedgehog signaling to initiate medulloblastoma (MB), a tumor of the cerebellum. By combining SB mutagenesis with Patched1 heterozygous mice (Ptch1lacZ/+), we observed an increased frequency of MB and decreased tumor-free survival compared with Ptch1lacZ/+ controls. From an analysis of 85 tumors, we identified 77 common insertion sites that map to 56 genes potentially driving increased tumorigenesis. The common insertion site genes identified in the mutagenesis screen were mapped to human orthologs, which were used to select probes and corresponding expression data from an independent set of previously described human MB samples, and surprisingly were capable of accurately clustering known molecular subgroups of MB, thereby defining common regulatory networks underlying all forms of MB irrespective of subgroup. We performed a network analysis to discover the likely mechanisms of action of subnetworks and used an in vivo model to confirm a role for a highly ranked candidate gene, Nfia, in promoting MB formation. Our analysis implicates candidate cancer genes in the deregulation of apoptosis and translational elongation, and reveals a strong signature of transcriptional regulation that will have broad impact on expression programs in MB. These networks provide functional insights into the complex biology of human MB and identify potential avenues for intervention common to all clinical subgroups.

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