Stolzenberg M C, Brugières L, Gardes M, Dessarps-Freichey F, Chompret A, Bressac B, Lenoir G, Bonaïti-Pellié C, Lemerle J, Feunteun J
Laboratoire d'Oncologie Moléculaire, CNRS URA 1158, Institut Gustave Roussy, Villejuif, France.
Oncogene. 1994 Oct;9(10):2799-804.
Germline p53 mutations have been detected in approximately half of the families affected by the Li-Fraumeni syndrome (LFS), in which they are believed to represent the genetic status predisposing to multiple cancers. Failure to detect mutations in the other half of LFS families suggests that sequence analysis, which has been limited to the p53 gene coding region, have overlooked other genetic events lying outside of this region or/and that alterations in other gene(s) than p53 may also lead to the syndrome. In this report, we present the evidence that a single base pair deletion in the p53 coding sequence, leading to premature signal termination of translation, generates a null allele by preventing transport of mutant allele mRNAs into the cytoplasm. This allelic exclusion which confers a status of unizygote vis-à-vis the wild-type p53 gene to individuals who carry the mutant allele, leads to predisposition to multiple cancers in a Li-Fraumeni family. Thus, the loss of the wild-type p53 allele appears as the rate limiting step in tumor induction.
在大约一半受李-佛美尼综合征（LFS）影响的家族中检测到种系p53突变，据信这些突变代表了易患多种癌症的遗传状态。在另一半LFS家族中未检测到突变，这表明仅限于p53基因编码区的序列分析忽略了该区域之外的其他遗传事件，和/或除p53之外的其他基因的改变也可能导致该综合征。在本报告中，我们提供了证据表明，p53编码序列中的单个碱基对缺失导致翻译提前信号终止，通过阻止突变等位基因mRNA转运到细胞质中产生无效等位基因。这种等位基因排斥使携带突变等位基因的个体相对于野生型p53基因处于纯合子状态，导致李-佛美尼家族易患多种癌症。因此，野生型p53等位基因的缺失似乎是肿瘤诱导中的限速步骤。
