Methylation Status of the Chromosome Arm 19q MicroRNA Cluster in Sporadic and Androgenetic-Biparental Mosaicism-Associated Hepatic Mesenchymal Hamartoma
Methylation Status of the Chromosome Arm 19q MicroRNA Cluster in Sporadic and Androgenetic-Biparental Mosaicism-Associated Hepatic Mesenchymal Hamartoma
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DOI：
10.2350/15-01-1600-oa.1
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发表时间：
2015-05-01
影响因子：
1.9
通讯作者：
Kapur, Raj P.
中科院分区：
文献类型：
--
作者：
Keller, Rachel B.;El Demellawy, Dina;Kapur, Raj P.
染色体带19q13.4上的C19 MC基因编码一簇46个microRNA;这些microRNA通常仅在父亲等位基因和胎盘中表达。胎盘表达与父亲C19 MC启动子的选择性去甲基化相关，而非胎盘组织中母亲和父亲等位基因的甲基化相反。先前的研究表明，在大多数肝间叶错构瘤中，该基因的“异位”激活，包括散发性肿瘤和其他具有雄激素-双亲嵌合体的肿瘤（细胞亚群是二倍体，但仅包含父系来源的染色体）。在目前对14例间充质错构瘤C19 MC启动子甲基化状态的研究中，在6例肿瘤中发现了去甲基化等位基因，包括所有4例雄激素-双亲嵌合体。相反，只有甲基化的等位基因被克隆从散发性错构瘤，包括3个肿瘤与染色体重排认为可能激活C19 MC表达的天然启动子无关。结合已发表的数据，研究结果表明肝脏间叶性错构瘤中C19 MC激活的多种分子机制，包括在一个病例子集中间叶细胞中存在正常的胎盘印迹模式。后一种错构瘤的部分或全部可能由胎盘“移植”引起，这一假说得到了胎盘血管标记物葡萄糖转运蛋白-1的内皮表达的支持，在6例脱甲基等位基因病例中有1例。
The C19MC gene on chromosome band 19q13.4 encodes a cluster of 46 microRNAs; those microRNAs are normally only expressed from the paternal allele and in the placenta. Placental expression correlates with selective demethylation of the paternal C19MC promoter, in contrast to methylation of both maternal and paternal alleles in nonplacental tissues. Prior investigations demonstrated "ectopic'' activation of this gene in most hepatic mesenchymal hamartomas, including sporadic tumors and others with androgenetic-biparental mosaicism ( subset of cells are diploid, but contain only paternally derived chromosomes). In the present investigation of C19MC promoter methylation status in a series of 14 mesenchymal hamartomas, a demethylated allele was identified in 6 tumors, including all 4 with androgenetic-biparental mosaicism. Conversely, only methylated alleles were cloned from sporadic hamartomas, including 3 tumors with chromosomal rearrangements thought likely to activate C19MC expression independent of the native promoter. In conjunction with published data, the findings suggest multiple molecular mechanisms for C19MC activation in hepatic mesenchymal hamartoma, including the existence of a normal placental imprinting pattern in mesenchymal cells in a subset of cases. Some or all of the latter hamartomas may result from placental "grafting,'' a hypothesis supported by endothelial expression of the placental vascular marker, glucose transporter-1, in 1 of the 6 cases with a demethylated allele.