Kapur Raj P, Berry Jessica E, Tsuchiya Karen D, Opheim Kent E
1 Department of Laboratories, Seattle Children's Hospital, Seattle, WA, USA.
Pediatr Dev Pathol. 2014 Mar-Apr;17(2):75-84. doi: 10.2350/13-12-1415-OA.1. Epub 2014 Feb 20.
Recurrent genetic alterations found in hepatic mesenchymal hamartoma include either androgenetic-biparental mosaicism or chromosomal rearrangements involving chromosome 19q13.4, in the vicinity of the chromosome 19q microRNA cluster (C19MC). Abnormal activation of C19MC, which is subject to paternal imprinting and is normally expressed only in placenta, could account for both genetic associations because androgenetic cells carry only paternal chromosomes. In this study, a 4.2-Mb deletion involving the 5'-end of C19MC was detected in a sporadic mesenchymal hamartoma by chromosomal microarray. Fluorescence in situ hybridization studies showed that the deletion localized to mesenchymal cells in the stroma of the hamartoma. Quantitative real-time polymerase chain reaction analysis of this tumor, 9 other sporadic hepatic mesenchymal hamartomas, and 3 hamartomas associated with androgenetic-biparental mosaicism demonstrated C19MC microRNA expression in all but 2 sporadic cases, with no significant expression in control liver. The findings support a pathogenetic model for mesenchymal hamartoma as a consequence of "ectopic" activation of C19MC in hepatic stroma, due to either chromosomal rearrangements or paternal uniparental disomy.
肝间叶性错构瘤中发现的复发性基因改变包括孤雄二倍体-双亲嵌合体或涉及19号染色体q13.4区域（在19号染色体q微小RNA簇（C19MC）附近）的染色体重排。C19MC的异常激活可能解释了这两种基因关联，因为C19MC受父系印记调控且通常仅在胎盘中表达，而孤雄细胞仅携带父系染色体。在本研究中，通过染色体微阵列在一例散发的间叶性错构瘤中检测到一个涉及C19MC 5'端的4.2Mb缺失。荧光原位杂交研究表明，该缺失定位于错构瘤间质中的间叶细胞。对该肿瘤、另外9例散发的肝间叶性错构瘤以及3例与孤雄二倍体-双亲嵌合体相关的错构瘤进行定量实时聚合酶链反应分析，结果显示除2例散发病例外，所有病例中均有C19MC微小RNA表达，而在对照肝脏中无明显表达。这些发现支持了一种发病机制模型，即由于染色体重排或父系单亲二体导致肝间质中C19MC“异位”激活，从而引发间叶性错构瘤。
