Liu Wennuan, Ewing Charles M, Chang Bao-Li, Li Tao, Sun Jishan, Turner Aubrey R, Dimitrov Latchezar, Zhu Yi, Sun Jielin, Kim Jin Woo, Zheng S Lilly, Isaacs William B, Xu Jianfeng
Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Genes Chromosomes Cancer. 2007 Nov;46(11):972-80. doi: 10.1002/gcc.20482.
A number of TMPRSS2/ERG fusion transcripts have been reported since the discovery that recurrent genomic rearrangements result in the fusion of TMPRSS2 and ETS family member genes. In this article we present evidence demonstrating that multiple genomic alterations contribute to the formation of various TMPRSS2/ERG transcripts. Using allele-specific analysis of the data generated from the GeneChip 500K SNP array we observed both hemizygous and homozygous deletions occurring at different locations between and within TMPRSS2 and ERG in prostate cancers. The 500K SNP array enabled us to fine map the start and end of each deletion to specific introns of these two genes, and to predict a variety of fusion transcripts, including a new form which was confirmed by sequence analysis of the fusion transcripts in various tumors. We also inferred that translocation is an additional mechanism of fusion for these two genes in some tumors, based on largely diploid genomic DNA between TMPRSS and ERG, and different fusion transcripts produced in these tumors. Using a bioinformatics approach, we then uncovered the consensus sequences in the regions harboring the breakpoints of the deletions. These consensus sequences were homologous to the human Alu-Sq and Alu-Sp subfamily consensus sequences, with more than 80% homology. The presence/absence of Alu family consensus sequence in the introns of TMPRSS2 and ERG correlates with the presence/absence of fusion transcripts of theses two genes, indicating that these consensus sequences may contribute to genomic deletions and the fusion of TMPRSS2 and ERG in prostate cancer.
自从发现复发性基因组重排导致TMPRSS2和ETS家族成员基因融合以来，已经报道了许多TMPRSS2/ERG融合转录本。在本文中，我们提供证据证明多种基因组改变促成了各种TMPRSS2/ERG转录本的形成。通过对基因芯片500K SNP阵列产生的数据进行等位基因特异性分析，我们观察到前列腺癌中TMPRSS2和ERG之间以及内部不同位置发生了半合子和纯合子缺失。500K SNP阵列使我们能够将每个缺失的起始和结束位置精确映射到这两个基因的特定内含子，并预测各种融合转录本，包括一种新形式，该形式通过对各种肿瘤中融合转录本的序列分析得到了证实。基于TMPRSS和ERG之间基本为二倍体的基因组DNA以及这些肿瘤中产生的不同融合转录本，我们还推断易位是某些肿瘤中这两个基因融合的另一种机制。然后，我们使用生物信息学方法，在包含缺失断点的区域中发现了共有序列。这些共有序列与人类Alu-Sq和Alu-Sp亚家族共有序列同源，同源性超过80%。TMPRSS2和ERG内含子中Alu家族共有序列的有无与这两个基因融合转录本的有无相关，表明这些共有序列可能促成前列腺癌中基因组缺失以及TMPRSS2和ERG的融合。
