Watanabe K, Sato K, Biernat W, Tachibana O, von Ammon K, Ogata N, Yonekawa Y, Kleihues P, Ohgaki H
Unit of Molecular Pathology, IARC, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France.
Clin Cancer Res. 1997 Apr;3(4):523-30.
Mutations of the p53 tumor suppressor gene are a genetic hallmark of human astrocytic neoplasms, but their predictive role in glioma progression is still poorly understood. We analyzed 144 biopsies from 67 patients with recurrent astrocytoma by single-strand conformation polymorphism and direct DNA sequencing. We found that 46 of 67 patients (69%) had a p53 mutation in at least one biopsy. In 41 of these (89%), the mutation was already present in the first biopsy, indicating that p53 mutations are early events in the evolution of diffuse astrocytomas. Double mutations of the p53 gene were observed in three tumors and also present from the first biopsy. Of 28 low-grade astrocytomas with a p53 mutation, 7 (25%) showed loss of the normal allele in the first biopsy. The allele status remained the same in 95% of the cases, irrespective of whether the recurrent lesion had the same or a higher grade of malignancy. Progression of low-grade astrocytomas to anaplastic astrocytoma or glioblastoma occurred at a similar frequency in lesions with (79%) and without (63%) p53 mutations (P = 0.32), indicating that this genetic alteration is associated with tumor recurrence but not predictive of progression to a more malignant phenotype. However, the time interval until progression was shorter in patients with low-grade astrocytomas carrying a p53 mutation (P = 0.055).
p53肿瘤抑制基因的突变是人类星形细胞瘤的一个遗传特征，但其在胶质瘤进展中的预测作用仍知之甚少。我们通过单链构象多态性和直接DNA测序分析了67例复发性星形细胞瘤患者的144份活检样本。我们发现，67例患者中有46例（69%）至少在一份活检样本中存在p53突变。其中41例（89%）在首次活检时就已存在该突变，这表明p53突变是弥漫性星形细胞瘤演变过程中的早期事件。在三个肿瘤中观察到p53基因的双重突变，且同样在首次活检时就已存在。在28例有p53突变的低级别星形细胞瘤中，7例（25%）在首次活检时显示正常等位基因缺失。在95%的病例中，等位基因状态保持不变，无论复发病变的恶性程度相同或更高。有p53突变（79%）和无p53突变（63%）的低级别星形细胞瘤进展为间变性星形细胞瘤或胶质母细胞瘤的频率相似（P = 0.32），这表明这种基因改变与肿瘤复发相关，但不能预测向更恶性表型的进展。然而，携带p53突变的低级别星形细胞瘤患者进展前的时间间隔较短（P = 0.055）。
