Genomic amplification of orthodenticle homologue 2 in medulloblastomas.
Genomic amplification of orthodenticle homologue 2 in medulloblastomas.
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DOI：
10.1158/0008-5472.703.65.3
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发表时间：
2005-02
期刊：
影响因子：
11.2
通讯作者：
K. Boon;C. Eberhart;G. Riggins
中科院分区：
文献类型：
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作者：
K. Boon;C. Eberhart;G. Riggins
为了更好地了解髓母细胞瘤发展的遗传基础，我们使用数字核型分析结合表达分析来寻找这些肿瘤中的基因组扩增和缺失。通过对每次分析平均 195,745 个基因组 DNA 标签进行测序，对 5 个髓母细胞瘤基因组进行核型分析。标签在独特的位置进行计数，并映射到人类基因组，以确定沿每条染色体的高分辨率 DNA 拷贝数。通常与髓母细胞瘤相关的基因组改变（包括 MYC 扩增和等染色体 17q）很容易检测到。令人惊讶的是，仅对五个基因组的分析就揭示了染色体 14q 上的新扩增子，其中一个包含正牙齿同源物 2 (OTX2) 同源盒基因。 DNA拷贝数分析显示OTX2在11个髓母细胞瘤细胞系中的2个和42个原发性肿瘤中的8个中经历了基因组扩增。 14q 扩增子中 OTX2 侧翼的三个基因和预测的开放阅读框在其他 9 个扩增子中至少有一个没有扩增，这表明 OTX2 作为基因靶标具有选择性优势。 OTX2基因的扩增程度从8个拷贝到超过50个拷贝不等。 OTX2转录本在髓母细胞瘤或发育细胞中高度特异性表达。对 240 种不同人类肿瘤或正常组织的基因表达进行系列分析表明，测序的所有 783 个 OTX2 转录物中 96% 存在于髓母细胞瘤或胚胎干细胞中。 OTX2 的功能是指定发育中大脑各个区域的神经外胚层的命运。这种发育作用与 OTX2 是髓母细胞瘤癌基因的证据一致。
To better understand the genetic basis of medulloblastoma development, we sought genomic amplifications and deletions in these tumors using digital karyotyping in combination with expression analysis. Five medulloblastoma genomes were karyotyped by sequencing an average of 195,745 genomic DNA tags for each analysis. Tags were tallied at unique positions and mapped to the human genome to determine DNA copy numbers in high resolution along each chromosome. Genomic alterations normally associated with medulloblastomas, including MYC amplification and isochromosome 17q, were easily detected. Surprisingly, analysis of only five genomes revealed novel amplicons on chromosome 14q, one of which contained the orthodenticle homologue 2 (OTX2) homeobox gene. DNA copy number analysis showed that OTX2 had undergone genomic amplification in 2 of 11 medulloblastoma cell lines and 8 of 42 primary tumors. The three genes and a predicted open reading frame flanking OTX2 in the 14q amplicon were not amplified in at least one of the other nine amplicons, implicating OTX2 as the gene target conferring a selective advantage. The degree of OTX2 amplification ranged from 8 copies to over 50 copies of the gene. OTX2 transcript was highly and specifically expressed in medulloblastoma or developing cells. Serial analysis of gene expression of 240 different human tumors or normal tissues revealed that 96% of all 783 OTX2 transcripts sequenced were in medulloblastomas or embryonic stem cells. OTX2 functions to specify the fate of neuroectoderm in various regions of the developing brain. This developmental role is consistent with the evidence suggesting that OTX2 is a medulloblastoma oncogene.