Clonal expansion and attenuated apoptosis in Wilms' tumors are associated with p53 gene mutations.
Clonal expansion and attenuated apoptosis in Wilms' tumors are associated with p53 gene mutations.
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发表时间：
1995-01
期刊：
影响因子：
11.2
通讯作者：
Nabeel Bardeesy;J. Beckwith;Jerry Pelletier
中科院分区：
文献类型：
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作者：
Nabeel Bardeesy;J. Beckwith;Jerry Pelletier
p53基因产物是激活由癌基因和细胞毒性剂触发的凋亡途径所必需的。肾母细胞瘤是一种儿童肾脏恶性肿瘤，它为评估肿瘤进展中的遗传事件提供了一个范例。这种恶性肿瘤通常与p53突变无关，即使在晚期疾病状态下，对目前的治疗方案也非常敏感。然而，肾母细胞瘤的间变性组织学变体经常与p53基因突变相关，并且显示出不良预后。我们分析了7个肾母细胞瘤，我们配对的样本从非间变性和间变性地区。在这些肿瘤中的6个中检测到p53突变，其中5个显示突变仅限于间变性区域。第六个样本的非间变性细胞为p53突变杂合，而该肿瘤的间变性区域显示减少为纯合性。这些结果表明，向间变性的进展与已经获得p53突变的细胞的克隆扩增相关。我们证明，p53突变的肿瘤细胞表现出衰减的凋亡，这表明这种病变可能提供了一个选择性的优势，在体内减少细胞死亡。
The p53 gene product is required for activation of an apoptotic pathway triggered by oncogenes and cytotoxic agents. Wilms' tumor, a pediatric renal malignancy, provides a paradigm for evaluating genetic events involved in tumor progression. This malignancy is generally not associated with p53 mutations, and even in advanced disease states is quite responsive to current treatment regimens. The anaplastic histological variant of Wilms' tumor, however, is frequently associated with p53 gene mutations and shows poor prognosis. We analyzed seven Wilms' tumors for which we had paired samples from nonanaplastic and anaplastic regions. p53 mutations were detected in six of these tumors, five of which demonstrated mutations restricted to anaplastic regions. Nonanaplastic cells of the sixth sample were heterozygous for a p53 mutation, whereas the anaplastic area of this tumor showed reduction to homozygosity. These results indicate that progression to anaplasia is associated with clonal expansion of cells which have acquired a p53 mutation. We demonstrated that tumor cells with p53 mutations show attenuated apoptosis, suggesting that such lesions may provide a selective advantage in vivo by decreasing cell death.