Pritchard-Jones K, Fleming S
Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, UK.
Oncogene. 1991 Dec;6(12):2211-20.
Wilms' tumour (nephroblastoma), a childhood embryonal kidney tumour, is believed to arise from malignant transformation of abnormally persistent metanephric blastemal cells. At a histological level, tumours show a remarkable mimicry of the normal nephrogenic pathway. There is histological and epidemiological evidence for at least two pathogenetic groupings within Wilms' tumour which may reflect different timings of the tumorigenic insult in this pathway and/or involvement of different genes. Tumorigenesis is thought to result from loss of function of a so-called tumour-suppressor gene which has an essential role in control of normal genitourinary development. Such a candidate, Wilms' tumour gene (WT1) mapping to chromosome 11p13, has been isolated and is known to be mutated in some tumours. We have examined the cell types expressing this gene in 32 Wilms' tumours and in nephroblastomatosis by in situ mRNA hybridization. Our results show that WT1 is expressed only in neoplastic structures whose normal counterparts also express the gene and that abnormally persistent high levels of expression are common in both these lesions. Thus, WT1 expression is a good marker for tumour differentiation and reveals how the normal pattern of differentiation is disrupted in Wilms' tumours. We postulate that mutation of the WT1 gene at the 11p13 locus results in Wilms' tumours associated with intralobar nephrogenic rests, which frequently show stromal-predominant histology. We have used our results and ideas to reinterpret current theories on tumour histogenesis and propose a model which explains how patterns of epithelial differentiation are disrupted in Wilms' tumour and how malignant stroma can result from mutation in WT1.
肾母细胞瘤（肾胚胎瘤）是一种儿童期胚胎性肾肿瘤，被认为是由异常持续存在的后肾胚基细胞恶性转化而来。在组织学水平上，肿瘤表现出对正常肾发生途径的显著模仿。有组织学和流行病学证据表明，肾母细胞瘤内至少存在两种致病分组，这可能反映了该途径中致瘤性损伤的不同时间和/或不同基因的参与。肿瘤发生被认为是由于一种所谓的肿瘤抑制基因功能丧失所致，该基因在正常泌尿生殖系统发育的控制中起关键作用。这样一个候选基因，即定位于11号染色体p13区域的肾母细胞瘤基因（WT1），已被分离出来，并且已知在一些肿瘤中发生了突变。我们通过原位mRNA杂交研究了32例肾母细胞瘤和肾母细胞瘤病中表达该基因的细胞类型。我们的结果表明，WT1仅在其正常对应物也表达该基因的肿瘤结构中表达，并且在这两种病变中异常持续的高水平表达都很常见。因此，WT1表达是肿瘤分化的良好标志物，并揭示了肾母细胞瘤中正常分化模式是如何被破坏的。我们推测，11号染色体p13位点的WT1基因突变导致与叶内肾源性残留相关的肾母细胞瘤，后者通常表现为以基质为主的组织学特征。我们利用我们的结果和观点重新解释了当前关于肿瘤组织发生的理论，并提出了一个模型，该模型解释了肾母细胞瘤中上皮分化模式是如何被破坏的，以及WT1突变如何导致恶性基质的形成。
