TMPRSS2 fusions with oncogenic ETS factors in prostate cancer involve unbalanced genomic rearrangements and are associated with HDAC1 and epigenetic reprogramming
TMPRSS2 fusions with oncogenic ETS factors in prostate cancer involve unbalanced genomic rearrangements and are associated with HDAC1 and epigenetic reprogramming
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DOI：
10.1158/0008-5472.can-06-1986
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发表时间：
2006-11-01
期刊：
影响因子：
11.2
通讯作者：
Kallioniemi, Olli
中科院分区：
文献类型：
--
作者：
Iljin, Kristiina;Wolf, Maija;Kallioniemi, Olli
将强雄激素反应基因TMPRSS2与ERG或其他致癌ETS因子融合的易位可能会促进前列腺癌的发展。在这里，我们研究了18个晚期前列腺癌的ETS因子改变，使用逆转录-聚合酶链式反应和DNA和RNA阵列技术，并从410个前列腺癌样本的微阵列数据中确定了可能的ERG下游基因靶点。在27个ETS因子中，ERG最常过度表达。7例TMPRSS2：ERG基因融合，1例TMPRSS2：ETV4融合。在6个ERG高表达的肿瘤中，5个ARRAY-CGH分析显示TMPRSS2和ERG基因座之间的间质2.8Mb缺失，或较小的不平衡重排。电子计算机分析显示，ERG基因共表达模式与组蛋白脱乙酰基酶1基因的高表达及其靶基因的低表达有关。此外，我们观察到WNT相关通路的表达增加，肿瘤坏死因子和细胞死亡通路的下调。总之，我们的数据表明，TMPRSS2：ERG易位在晚期前列腺癌中很常见，并通过不平衡的基因组重排发生。通过与TMPRSS2融合激活ERG可能导致表观遗传重编程、WNT信号转导和细胞死亡途径的下调，从而暗示ERG与癌症的几个特征有关，具有潜在的治疗意义。
Translocations fusing the strong androgen-responsive gene, TMPRSS2, with ERG or other oncogenic ETS factors may facilitate prostate cancer development. Here, we studied 18 advanced prostate cancers for ETS factor alterations, using reverse transcription-PCR and DNA and RNA array technologies, and identified putative ERG downstream gene targets from the microarray data of 410 prostate samples. Out of the 27 ETS factors, ERG was most frequently overexpressed. Seven cases showed TMPRSS2:ERG gene fusions, whereas the TMPRSS2:ETV4 fusion was seen in one case. In five out of six tumors with high ERG expression, array-CGH analysis revealed interstitial 2.8 Mb deletions between the TMPRSS2 and ERG loci, or smaller, unbalanced rearrangements. In silico analysis of the ERG gene coexpression patterns revealed an association with high expression of the histone deacetylase 1 gene, and low expression of its target genes. Furthermore, we observed increased expression of WNT-associated pathways and down-regulation of tumor necrosis factor and cell death pathways. In summary, our data indicate that the TMPRSS2:ERG translocation is common in advanced prostate cancer and occurs by virtue of unbalanced genomic rearrangements. Activation of ERG by fusion with TMPRSS2 may lead to epigenetic reprogramming, WNT signaling, and down-regulation of cell death pathways, implicating ERG in several hallmarks of cancer with potential therapeutic importance.