甲状腺乳头状癌中p53蛋白三维空间结构改变的临床病理研究

Clinicopathologic significance of structural alterations of p53 protein in papillary thyroid carcinoma

目的 深入研究p5 3蛋白空间结构的改变在甲状腺乳头状癌 (PTC)中的临床病理意义 ,为PTC的恶性度评价提供客观的指标。方法 采用PCR SSCP、DNA序列分析、以及利用国际共享资源计算机重构p5 3蛋白三维空间结构和有关分析软件等技术对 4 1例PTC进行分析。结果 p5 3基因突变Ⅰ组 (15例 )和未突变Ⅱ组 (2 6例 )的年龄、性别、原发瘤大小 (T)、淋巴结转移率 (N)和远处转移率 (M)无明显差异 (P >0 0 5 )。 9例 (9/ 15 ,Ⅰb组 )的氨基酸残基突变表现为核心功能域和碱性域的变化或核心功能域严重缺损。p5 3蛋白核心功能域结构的改变能直接抑制它与靶DNA的结合 ;碱性域结构的改变能间接抑制p5 3蛋白与靶DNA的结合。 6例 (6 / 15 ,Ⅰa组 )的氨基酸残基突变位于功能域之外。Ⅰb组的淋巴结转移率 (77 78% )明显高于Ⅰa组 (P <0 0 1) ,Ⅰb组的远处转移率(5 5 5 6 % )高于Ⅰa组 (P <0 0 5 )。结论 p5 3蛋白三维空间结构的改变是PTC演进与异质化的形态学基础之一 。

Objective To make a thorough study on the clinicopathologic significance of the three dimensional structural alteration of the p53 protein in papillary thyroid carcinomas and to provide an objective criterion for the evaluation of PTC prognosis. Methods A total of 41 PTC cases were enrolled Techniques including polymerase chain reaction with single strand conformational polymorphism (PCR SSCP), DNA sequencing, computerized three dimensional protein modeling by means of international shared resources and related software analysis were used. Results 15 cases with p53 gene mutation defined as Group Ⅰ were detected in totally 41 PTC cases No p53 gene mutation was found in the rest 26 cases which were classified as Group Ⅱ. The differences in lymph node metastatic rate, distant metastatic rate, age, sex, size of the lesion between Group Ⅰ and Group Ⅱ were not significant ( P >0 05) The alterations of the amino acid residues of 9 PTC cases out of the 15 p53 gene mutated patients (Group Ⅰ) were either located in the p53 protein domains, mainly the core domain and the non specific DNA binding basic domain, or the severely defect cases with the formation of widely divergent structures It was found that the alterations of the structure of the core domain could directly check the binding of p53 protein to its target DNA molecules In addition, the alterations of the structure of the basic domain could indirectly prohibit the binding The ones mentioned above were classified as Group Ⅰb The rest of six cases with their p53 protein amino acid residues mutated beyond the domains were grouped as Group Ⅰa The differences in lymph node metastatic rate, distant metastatic rate between Group Ⅰb and Group Ⅰa were statistically significant ( P <0 01, P <0 05) respectively. Conclusions The alterations of the three dimensional structure of p53 protein is considered as one of the morphological basis of the progression and heterogeneity of PTC They render an authentic evidence for the selection of the clinical cases with a poor risk for metastasis