Frequency and timing of loss of imprinting at 11p13 and 11p15 in Wilms' tumor development
Frequency and timing of loss of imprinting at 11p13 and 11p15 in Wilms' tumor development
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DOI：
10.1158/1541-7786.mcr-08-0002
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发表时间：
2008-07-01
影响因子：
5.2
通讯作者：
Malik, Karim T. A.
中科院分区：
文献类型：
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作者：
Brown, Keith W.;Power, Frances;Malik, Karim T. A.
Wilms'肿瘤（WT）中经常发生表观遗传变化，特别是11p15位点1GF2/H19印迹丢失（LOI）。我们之前的研究结果已经从11p13的WT1位点发现了印迹转录本（WT1- as和AWT1），并在一些WTs中显示了这些印迹转录本的LOI。在这篇文章中，我们开始测试11p13和11p15的LOI与它们在WT进展中相对于其他遗传变化的时间之间的关系。我们发现WT中11p13 LOI的水平（83%）高于11p15 LOI（71%）。11p13和11p15差异甲基化区域的甲基化水平以及WT1-AS/AWT1和IGF2等位基因表达之间没有相关性。有趣的是，11p13正常印记的保留与一小部分相对晚发的高阶段WTs有关。对肾源性位点遗传和表观遗传改变的研究表明，11p13和11p15位点的LOI发生在16q杂合性缺失（LOH）或7p LOH之前。这表明，这些LOH事件不太可能是LOI的原因，但LOH可能通过增强由LOI引起的IGF2和/或WT1-AS/AWT1过表达的影响而起作用。
Epigenetic changes occur frequently in Wilms' tumor (WT), especially loss of imprinting (LOI) of 1GF2/H19 at 11p15. Our previous results have identified imprinted transcripts (WT1-AS and AWT1) from the WT1 locus at 11p13 and showed LOI of these in some WTs. In this article, we set out to test the relationship between LOI at 11 p13 and 11 p15 and their timing in WT progression relative to other genetic changes. We found a higher level (83%) of 11 p13 LOI in WT than of 11 p15 LOI (71%). There was no correlation between methylation levels at the 11 p13 and 11 p15 differentially methylated regions or between allelic expression of WT1-AS/AWT1 and IGF2. Interestingly, retention of normal imprinting at 11p13 was associated with a small group of relatively late-onset, high-stage WTs. An examination of genetic and epigenetic alterations in nephrogenic rests, which are premalignant WT precursors, showed that LOI at both 11 p13 and 11 p15 occurred before either 16q loss of heterozygosity (LOH) or 7p LOH. This suggests that these LOH events are very unlikely to be a cause of LOI but that LOH may act by potentiating the effects of overexpression of IGF2 and/or WT1-AS/AWT1 that result from LOI.