Department of Surgery, The Pediatric Brain Tumor Foundation Institute, and The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Veterans Affairs Medical Center, Durham, North Carolina 27710, USA.
Cancer Res. 2010 Jan 1;70(1):181-91. doi: 10.1158/0008-5472.CAN-09-2331. Epub 2009 Dec 22.
OTX2 is a developmentally regulated transcription factor involved in early morphogenesis of the central nervous system. This gene is amplified and overexpressed in medulloblastoma cell lines, but the nature and extent of its genetic alterations in primary tumors have not been evaluated. Analysis of a large cohort of primary medulloblastomas revealed frequent focal copy number gain of a region minimally containing OTX2 as a single gene. OTX2 copy number gain was restricted to tumor subtypes that did not express a molecular signature of Wnt or Shh pathway activation. FISH analysis revealed copy number gain in a subset of cells within medulloblastoma samples, suggesting a late event in tumor progression. Gain of OTX2 copy number was associated with the presence of anaplastic histologic features and shorter survival in medulloblastoma patients. In support of a functional role, ectopic OTX2 expression enhanced proliferation and tumorigenicity of immortalized primary cells, whereas OTX2 knockdown in medulloblastoma cells prolonged the survival of animals bearing xenograft tumors. Mechanistic investigations revealed upregulation of MYC as a potential mechanism whereby OTX2 promotes tumor progression. Our findings define OTX2 as an important oncogenic driver in medulloblastoma.
OTX2 是一种发育调节转录因子，参与中枢神经系统的早期形态发生。该基因在成神经管细胞瘤细胞系中扩增和过表达，但在原发肿瘤中其遗传改变的性质和程度尚未得到评估。对大量原发性成神经管细胞瘤的分析显示，含有 OTX2 作为单个基因的最小区域的局部拷贝数获得频繁。OTX2 拷贝数增益仅限于不表达 Wnt 或 Shh 通路激活分子特征的肿瘤亚型。FISH 分析显示在成神经管细胞瘤样本中的一部分细胞中存在拷贝数增益，提示肿瘤进展中的晚期事件。OTX2 拷贝数增加与成神经管细胞瘤患者存在间变性组织学特征和较短的生存期相关。为支持其功能作用，异位 OTX2 表达增强了永生化原代细胞的增殖和致瘤性，而 OTX2 在成神经管细胞瘤细胞中的敲低延长了携带异种移植肿瘤的动物的存活时间。机制研究表明，MYC 的上调是 OTX2 促进肿瘤进展的潜在机制。我们的研究结果将 OTX2 定义为成神经管细胞瘤中的一个重要致癌驱动因子。
