Bardeesy N, Beckwith J B, Pelletier J
Department of Biochemistry, McGill University, Montreal, Canada.
Cancer Res. 1995 Jan 15;55(2):215-9.
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.
p53基因产物是激活由癌基因和细胞毒性药物引发的凋亡途径所必需的。肾母细胞瘤是一种儿童期肾脏恶性肿瘤，为评估肿瘤进展过程中涉及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，即使在疾病晚期对当前的治疗方案也相当敏感。然而，肾母细胞瘤的间变组织学变体经常与p53基因突变相关，且预后较差。我们分析了七个肾母细胞瘤，对于这些肿瘤我们有来自非间变和间变区域的配对样本。在其中六个肿瘤中检测到了p53突变，其中五个显示突变仅限于间变区域。第六个样本的非间变细胞对于p53突变是杂合的，而该肿瘤的间变区域显示为纯合性缺失。这些结果表明，向间变的进展与获得p53突变的细胞的克隆性扩增相关。我们证明，具有p53突变的肿瘤细胞显示凋亡减弱，这表明此类病变可能通过减少细胞死亡在体内提供选择性优势。
