Epigenetic specificity of loss of imprinting of the IGF2 gene in Wilms tumors
Epigenetic specificity of loss of imprinting of the IGF2 gene in Wilms tumors
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DOI：
10.1093/jnci/djm069
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发表时间：
2007-08-15
影响因子：
10.3
通讯作者：
Feinberg, Andrew P.
中科院分区：
文献类型：
--
作者：
Bjornsson, Hans T.;Brown, Lindsey J.;Feinberg, Andrew P.
IGF 2基因（编码胰岛素样生长因子11）的印记缺失（LOI）是肾母细胞瘤中最常见的遗传或表观遗传改变; LOI涉及正常抑制的母系遗传等位基因的异常激活。我们先前发现IGF 2的LOI发生在大约一半的Wilms肿瘤中（即，那些由谱系定向的肾祖细胞产生的细胞）。我们研究了IGF 2的LOI是否与IGF 2以外的位点的印记松弛或DNA甲基化的广泛改变有关。我们通过使用热终止逆转录聚合酶链反应和/或H19基因差异甲基化区域的甲基化分析，对59例肾母细胞瘤样本进行IGF 2 LOI状态分层，并确定了31例有LOI和28例无LOI的样本。我们使用定量等位基因特异性表达分析来确定其他六个印记基因（即，H19、KCNQ 1、LIT 1、TSSC 5、GRB 10和MEG 3）具有轻微的LOI。对于LIT 1、TSSC 5、GRB 10和MEG 3，在有或没有LOI的肾母细胞瘤之间没有发现等位基因特异性表达的统计学显著差异。对于KCNQ 1基因，有LOI组（37.0%，95%置信区间[CI] = 31.8%至42.2%）和无LOI组（27.7%，95% CI = 21.8%至33.5%）之间存在轻微差异（混合效应模型中组间差异F检验P = 0.02）。对于H19，我们还发现具有（7.5%，95%CI = 2.4%至12.7%）和不具有（2.2%，95%CI = -3.2%至7.6%）IGF 2 LOI的组之间存在轻微差异（F检验P = 0.15）。在27个肿瘤样本中，我们还使用微阵列技术分析了378个基因的甲基化，其中38个是疑似或确认的印迹基因。我们发现，只有H19基因差异甲基化区域的统计学显著性改变与IGF 2的LOI相关。因此，Wilms肿瘤中的表观遗传学改变并不普遍，支持IGF 2的LOI的基因和谱系特异性。
Loss of imprinting (LOI) of the IGF2 gene (which encodes insulin-like growth factor 11) is the most common genetic or epigenetic alteration in Wilms tumor; LOI involves aberrant activation of the normally repressed maternally inherited allele. We found previously that LOI of IGF2 occurs in approximately half of all Wilms tumors (i.e., those arising from lineage-committed nephrogenic progenitor cells). We investigated whether LOI of IGF2 is associated with relaxation of imprinting at loci other than IGF2 or with widespread alterations in DNA methylation. We stratified 59 Wilms tumor samples by IGF2 LOI status by use of hot-stop reverse transcription-polymerase chain reaction and/or methylation analysis of the differentially methylated region of the H19 gene and identified 31 samples with and 28 without LOI. We used quantitative allele-specific expression analysis to determine whether six other imprinted genes (i.e., H19, KCNQ1, LIT1, TSSC5, GRB10, and MEG3) had subtle LOI. No statistically significant difference in allele-specific expression between Wilms tumor with or without LOI was found for LIT1, TSSC5, GRB10, and MEG3. For the KCNQ1 gene there was a slight difference between the groups with (37.0%, 95% confidence interval [CI] = 31.8% to 42.2%) and without (27.7%, 95% CI = 21.8% to 33.5%) LOI (P = .02 for F test of group differences in a mixed-effects model). For H19, we also found a slight difference between the groups with (7.5%, 95% CI = 2.4% to 12.7%) and without (2.2%, 95% CI = -3.2% to 7.6%) LOI of IGF2 (P = .15 for F test). In 27 tumor samples, we also used a microarray technique to analyze methylation of 378 genes, 38 of which were suspected or confirmed imprinted genes. We found that statistically significant alterations in only the differentially methylated region of the H19 gene were associated with LOI of IGF2. Thus, epigenetic alterations in Wilms tumors are not widespread, supporting the gene and lineage specificity of LOI of IGF2.