OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas.
OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas.
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DOI：
10.1158/0008-5472.can-09-2331
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发表时间：
2010-01-01
期刊：
影响因子：
11.2
通讯作者：
Yan H
中科院分区：
文献类型：
--
作者：
Adamson DC;Shi Q;Wortham M;Northcott PA;Di C;Duncan CG;Li J;McLendon RE;Bigner DD;Taylor MD;Yan H
OTX2是一种发育调节的转录因子，在中枢神经系统的早期形态发生中发挥重要作用。我们先前在髓母细胞瘤细胞系中发现了OTX2的扩增和过表达。然而，在大样本的原发肿瘤中，OTX2基因改变的性质和频率尚未确定。为了加深我们对影响OTX2的基因组事件的理解，我们分析了大量原发髓母细胞瘤的基因组拷贝数和OTX2的mRNA表达。我们发现，在这些原发髓母细胞瘤中，最常见的局灶性拷贝数增加(在21%的肿瘤中获得，n=201)包含单一基因OTX2，表明OTX2拷贝数增加是该肿瘤的驱动事件。在这组肿瘤中，我们发现该事件仅限于不表达Wnt或Shh通路激活的分子特征的肿瘤亚型。FISH分析显示，在髓母细胞瘤样本中的一组细胞中存在OTX2拷贝数增加，这表明这是导致肿瘤进展的晚期事件。在髓母细胞瘤患者中，OTX2拷贝数的增加与间变性组织学特征的存在和较短的生存期有关。为了验证观察到的基因组事件的功能作用，我们证明了OTX2的异位表达促进了永生化原代细胞的增殖和致瘤性，并且OTX2在髓母细胞瘤异种移植中的敲除延长了受体动物的存活时间。最后，我们证明OTX2转录上调髓母细胞瘤癌基因MYC是OTX2促进肿瘤进展的潜在机制。
OTX2 is a developmentally regulated transcription factor that plays important roles in early morphogenesis of the central nervous system. We previously identified OTX2 amplification and overexpression in medulloblastoma cell lines. However, the nature and frequency of OTX2 genetic alterations have not been determined in large sample sizes of primary tumors. To refine our understanding of genomic events affecting OTX2, we analyzed genomic copy number and mRNA expression of OTX2 in a large cohort of primary medulloblastomas. We found that the most frequent focal copy number gain in these primary medulloblastomas (gained in 21% of the tumors, n=201) contained the single gene OTX2, indicating that copy number gain of OTX2 is a driver event in this tumor. In this cohort of tumors, we found that the event was restricted to tumor subtypes that do not express a molecular signature of either Wnt or Shh pathway activation. FISH analysis revealed that OTX2 copy number gain is present in a subset of cells within medulloblastoma samples, suggesting that it is a late event contributing to tumor progression. Gain of OTX2 copy number is associated with the presence of anaplastic histological features and shorter survival in medulloblastoma patients. To verify a functional role of the observed genomic events, we demonstrate that ectopic OTX2 expression enhances proliferation and tumorigenicity of immortalized primary cells and that OTX2 knockdown in medulloblastoma xenografts prolongs survival of recipient animals. Finally, we demonstrate that OTX2 transcriptionally upregulates the medulloblastoma oncogene MYC as a potential mechanism whereby OTX2 promotes tumor progression.