Guertl Barbara, Ratschek Manfred, Harms Dieter, Jaenig Ute, Leuschner Ivo, Poremba Christopher, Hoefler Gerald
Institute of Pathology, University of Graz, Graz, Austria.
Hum Pathol. 2003 Mar;34(3):278-81. doi: 10.1053/hupa.2003.32.
Nephrogenic rests (NRs), putative precursor lesions of nephroblastomas (Wilms' tumors), are found in 25% to 40% of kidneys presenting with nephroblastomas. Nephroblastomas are clonal tumors that, according to a genetic multistep model, are thought to arise as subclonal proliferations from NRs by accumulating genetic alterations. Different candidate genes for the pathogenesis of nephroblastomas have been identified, including those at chromosomes 11p13 (WT1 gene), 11p15 (WT2 gene), and 16q (WT3 gene). We investigated clonality and loss of heterozygosity (LOH) at these loci in different subtypes of NR. After microdissection under microscopic control, we analyzed a highly polymorphic locus of the human androgen receptor gene (HUMARA) for nonrandom X-inactivation of genomic DNA using a methylation-sensitive restriction enzyme to investigate clonality. Out of 14 patients, we found that 1 case each of adenomatous and hyperplastic NR and 2 of 7 cases of sclerosing NR were monoclonal. Five patients were noninformative. We assessed LOH at chromosomes 11p13, 11p15, and 16q by analyzing polymorphic gene loci at these regions. One hyperplastic NR and the corresponding tumor showed LOH at 11p13 and 11p15; 1 sclerosing NR and the corresponding tumor exhibited LOH at chromosome 16q. We demonstrate for the first time that sclerosing NRs can exhibit genetic alterations found in nephroblastomas, namely monoclonality and LOH at the WT gene loci. The histological morphology is no different between NRs with these genetic alterations and NRs without them. We conclude that these genetic changes are early events in the multistep genetic pathogenesis of nephroblastomas; however, they do not seem to fully determine a malignant potential of NR.
肾源性残留（NRs）是肾母细胞瘤（威尔姆斯瘤）的假定前体病变，在25%至40%的肾母细胞瘤病例的肾脏中可发现。肾母细胞瘤是克隆性肿瘤，根据遗传多步骤模型，被认为是通过积累基因改变从NRs作为亚克隆增殖而产生的。已经鉴定出肾母细胞瘤发病机制的不同候选基因，包括位于11号染色体p13（WT1基因）、11号染色体p15（WT2基因）和16号染色体q（WT3基因）上的基因。我们研究了不同亚型NRs在这些位点的克隆性和杂合性缺失（LOH）。在显微镜控制下进行显微切割后，我们使用甲基化敏感限制酶分析人类雄激素受体基因（HUMARA）的一个高度多态性位点，以研究基因组DNA的非随机X染色体失活，从而研究克隆性。在14例患者中，我们发现腺瘤样和增生性NRs各有1例，7例硬化性NRs中有2例是单克隆的。5例患者信息不明确。我们通过分析这些区域的多态性基因座来评估11号染色体p13、11号染色体p15和16号染色体q上的LOH。1例增生性NRs及其对应的肿瘤在11号染色体p13和11号染色体p15上显示LOH；1例硬化性NRs及其对应的肿瘤在16号染色体q上显示LOH。我们首次证明硬化性NRs可表现出肾母细胞瘤中发现的基因改变，即在WT基因座处的单克隆性和LOH。具有这些基因改变的NRs与没有这些改变的NRs在组织形态学上并无差异。我们得出结论，这些基因变化是肾母细胞瘤多步骤遗传发病机制中的早期事件；然而，它们似乎并不能完全决定NRs的恶性潜能。
