Reichel M B, Ohgaki H, Petersen I, Kleihues P
Institute of Neuropathology, University of Zürich, Switzerland.
Mol Carcinog. 1994 Feb;9(2):105-9. doi: 10.1002/mc.2940090208.
In a total of 26 primary human lung tumors and 60 metastases derived from them, exons 5-8 of the p53 tumor suppressor gene were analyzed by single-strand conformation polymorphism and subsequent direct DNA sequencing of amplified DNA. Mutational inactivation of the p53 gene was identified in four of five squamous cell carcinomas, three of nine adenocarcinomas, and two of nine small-cell carcinomas, the overall incidence being 35%. Point mutations occurred at a similar incidence in exons 5-8, with a preference for G-->T transversions. In seven of nine cases (78%), mutations were identical in the primary tumor and all of its metastases, indicating that in lung tumors, p53 mutations usually precede metastasis and that hematogenic and lymphogenic dissemination of tumor cells to other tissues is not associated with a selection against p53 inactivation. In one case, a kidney metastasis had the same mutation as the primary squamous cell carcinoma, whereas a liver metastasis had no mutation, indicating heterogeneity of the primary lung neoplasm and selective metastasis of mutated and nonmutated tumor cells to kidney and liver, respectively. Only in one liver metastasis was a mutation identified that was neither present in the primary lung tumor nor in a kidney metastasis, suggesting that occasionally p53 mutations occur after metastatic spread.
对总共26例原发性人类肺癌肿瘤及其60个转移灶进行研究，通过单链构象多态性分析及随后对扩增DNA进行直接DNA测序，分析了p53肿瘤抑制基因的第5至8外显子。在5例鳞状细胞癌中有4例、9例腺癌中有3例、9例小细胞癌中有2例发现了p53基因的突变失活，总体发生率为35%。第5至8外显子中发生点突变的发生率相似，以G→T颠换为主。在9例中的7例（78%）中，原发性肿瘤及其所有转移灶中的突变相同，这表明在肺癌中，p53突变通常先于转移发生，并且肿瘤细胞向其他组织的血行性和淋巴性播散与对p53失活的选择无关。在1例中，肾转移灶与原发性鳞状细胞癌具有相同的突变，而肝转移灶没有突变，这表明原发性肺肿瘤存在异质性，突变和未突变的肿瘤细胞分别选择性转移至肾和肝。仅在1例肝转移灶中发现了一种既不存在于原发性肺肿瘤也不存在于肾转移灶中的突变，这表明偶尔p53突变会在转移扩散后发生。
