Deducing the stage of origin of Wilms' tumours from a developmental series of Wt1-mutant mice.
Deducing the stage of origin of Wilms' tumours from a developmental series of Wt1-mutant mice.
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DOI：
10.1242/dmm.018523
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发表时间：
2015-08-01
影响因子：
4.3
通讯作者：
Hohenstein P
中科院分区：
文献类型：
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作者：
Berry RL;Ozdemir DD;Aronow B;Lindström NO;Dudnakova T;Thornburn A;Perry P;Baldock R;Armit C;Joshi A;Jeanpierre C;Shan J;Vainio S;Baily J;Brownstein D;Davies J;Hastie ND;Hohenstein P
肾母细胞瘤，即儿童肾癌，是正常发育受干扰而引发肿瘤的典型例子。从遗传学角度定义最明确的肾母细胞瘤亚组是由WT1肿瘤抑制基因双等位基因缺失所导致的那一组。在此，我们描述了一系列在肾单位发育的不同阶段（间充质向上皮转化（MET）前后）有条件地缺失Wt1的小鼠发育模型。我们证明了在研究的所有肾脏发育阶段，Wt1对正常发育至关重要。将来自突变小鼠模型的全基因组表达数据与具有突变型或野生型WT1数据集的人类肿瘤材料进行比较，确定了人类WT1突变型肿瘤的起源阶段，并强调了由于起源的发育阶段不同，两个人类肿瘤组之间存在根本差异。
总结：对不同肾单位特异性Wt1基因敲除小鼠模型的比较确定了人类WT1突变型肾母细胞瘤的起源阶段。
Wilms' tumours, paediatric kidney cancers, are the archetypal example of tumours caused through the disruption of normal development. The genetically best-defined subgroup of Wilms' tumours is the group caused by biallelic loss of the WT1 tumour suppressor gene. Here, we describe a developmental series of mouse models with conditional loss of Wt1 in different stages of nephron development before and after the mesenchymal-to-epithelial transition (MET). We demonstrate that Wt1 is essential for normal development at all kidney developmental stages under study. Comparison of genome-wide expression data from the mutant mouse models with human tumour material of mutant or wild-type WT1 datasets identified the stage of origin of human WT1-mutant tumours, and emphasizes fundamental differences between the two human tumour groups due to different developmental stages of origin. Summary: The comparison of different nephron-specific Wt1-knockout mouse models identifies the stage of origin of human WT1-mutant Wilms' tumours.