Koeman Julie M, Russell Ryan C, Tan Min-Han, Petillo David, Westphal Michael, Koelzer Katherine, Metcalf Julie L, Zhang Zhongfa, Matsuda Daisuke, Dykema Karl J, Houseman Heather L, Kort Eric J, Furge Laura L, Kahnoski Richard J, Richard Stéphane, Vieillefond Annick, Swiatek Pamela J, Teh Bin Tean, Ohh Michael, Furge Kyle A
Laboratory of Germline Modification and Cytogenetics, Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
PLoS Genet. 2008 Sep 5;4(9):e1000176. doi: 10.1371/journal.pgen.1000176.
Chromosomal abnormalities, such as structural and numerical abnormalities, are a common occurrence in cancer. The close association of homologous chromosomes during interphase, a phenomenon termed somatic chromosome pairing, has been observed in cancerous cells, but the functional consequences of somatic pairing have not been established. Gene expression profiling studies revealed that somatic pairing of chromosome 19 is a recurrent chromosomal abnormality in renal oncocytoma, a neoplasia of the adult kidney. Somatic pairing was associated with significant disruption of gene expression within the paired regions and resulted in the deregulation of the prolyl-hydroxylase EGLN2 [corrected] a key protein that regulates the oxygen-dependent degradation of hypoxia-inducible factor (HIF). Overexpression of EGLN2 [corrected] in renal oncocytoma increased ubiquitin-mediated destruction of HIF and concomitantly suppressed the expression of several HIF-target genes, including the pro-death BNIP3L gene. The transcriptional changes that are associated with somatic pairing of chromosome 19 mimic the transcriptional changes that occur following DNA amplification. Therefore, in addition to numerical and structural chromosomal abnormalities, alterations in chromosomal spatial dynamics should be considered as genomic events that are associated with tumorigenesis. The identification of EGLN2 as a significantly deregulated gene that maps within the paired chromosome region directly implicates defects in the oxygen-sensing network to the biology of renal oncocytoma.
染色体异常，如结构和数量异常，在癌症中很常见。在癌细胞中已观察到间期同源染色体的紧密关联，这一现象被称为体细胞染色体配对，但体细胞配对的功能后果尚未明确。基因表达谱研究表明，19号染色体的体细胞配对是成人肾脏肿瘤肾嗜酸细胞瘤中一种反复出现的染色体异常。体细胞配对与配对区域内基因表达的显著破坏有关，并导致脯氨酰羟化酶EGLN2（校正后）失调，EGLN2是调节缺氧诱导因子（HIF）氧依赖性降解的关键蛋白。肾嗜酸细胞瘤中EGLN2（校正后）的过表达增加了泛素介导的HIF破坏，并同时抑制了几个HIF靶基因的表达，包括促死亡基因BNIP3L。与19号染色体体细胞配对相关的转录变化模拟了DNA扩增后发生的转录变化。因此，除了染色体数量和结构异常外，染色体空间动力学的改变也应被视为与肿瘤发生相关的基因组事件。EGLN2被鉴定为一个在配对染色体区域内显著失调的基因，这直接表明氧传感网络的缺陷与肾嗜酸细胞瘤的生物学特性有关。
