Moulton T, Chung W Y, Yuan L, Hensle T, Waber P, Nisen P, Tycko B
Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Med Pediatr Oncol. 1996 Nov;27(5):476-83. doi: 10.1002/(SICI)1096-911X(199611)27:5<476::AID-MPO15>3.0.CO;2-8.
The selective loss of maternal and reduplication of paternal chromosome 11p15.5 alleles in Wilms' tumors (WTs) points to the existence of a paternally imprinted tumor suppressor gene(s) and/or a maternally imprinted dose-dependent growth-promoting gene(s) in this chromosomal region. Two reciprocally imprinted chromosome 11p15.5 genes, H19, a candidate tumor suppressor gene, and IGF2, a candidate dominant oncogene, have been well-characterized in terms of their imprinting and expression status in WTs. Here we review and extend data indicating that a majority of WTs show a bipaternal epigenotype at these loci, with H19 inactive and IGF2 biallelically active. This can arise either through loss of heterozygosity (LOH) or by a non-LOH pathway involving localized biallelic hypermethylation of H19 DNA. Conversion to this bipaternal endpoint has recently been found to affect not only these two genes, but also at least one other imprinted 11p15.5 gene, KIP2. Since 11p15.5 LOH and biallelic H19 hypermethylation can occur both early and late in tumor progression and since early loss is not associated with bilaterality or multifocality of WTs, these types of lesions appear to be permissive rather than rate-limiting in Wilms' tumorigenesis.
肾母细胞瘤（WTs）中母源染色体 11p15.5 等位基因的选择性缺失以及父源染色体 11p15.5 等位基因的重复，表明在该染色体区域存在一个父源印记的肿瘤抑制基因和/或一个母源印记的剂量依赖性生长促进基因。两个相互印记的染色体 11p15.5 基因，即候选肿瘤抑制基因 H19 和候选显性癌基因 IGF2，就其在肾母细胞瘤中的印记和表达状态已得到充分表征。在此，我们回顾并扩展相关数据，这些数据表明大多数肾母细胞瘤在这些位点呈现双父本表观基因型，其中 H19 无活性而 IGF2 双等位基因有活性。这可能通过杂合性缺失（LOH）或通过涉及 H19 DNA 局部双等位基因高甲基化的非 LOH 途径产生。最近发现，转变为这种双父本终点不仅会影响这两个基因，还会影响至少另一个印记的 11p15.5 基因 KIP2。由于 11p15.5 LOH 和双等位基因 H19 高甲基化可在肿瘤进展的早期和晚期发生，且早期缺失与肾母细胞瘤的双侧性或多灶性无关，因此这些类型的病变在肾母细胞瘤发生过程中似乎是允许性的而非限速性的。
