Malkin David
Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada.
Genes Cancer. 2011 Apr;2(4):475-84. doi: 10.1177/1947601911413466.
Li-Fraumeni syndrome (LFS) is a classic cancer predisposition disorder that is commonly associated with germline mutations of the p53 tumor suppressor gene. Examination of the wide spectrum of adult-onset and childhood cancers and the distribution of p53 mutations has led to a greater understanding of cancer genotype-phenotype correlations. However, the complex LFS phenotype is not readily explained by the simple identification of germline p53 mutations in affected individuals. Recent work has identified genetic events that modify the LFS phenotype. These include intragenic polymorphisms, mutations/polymorphisms of genes in the p53 regulatory pathway, as well as more global events such as aberrant copy number variation and telomere attrition. These genetic events may, in part, explain the breadth of tumor histiotypes within and across LFS families, the apparent accelerated age of onset within families, and the range of clinical outcomes among affected family members. This review will examine the clinical and genetic definitions of LFS and offer insight into how lessons learned from the study of this rare disorder may inform similar questions in other familial cancer syndromes.
李-弗劳梅尼综合征（LFS）是一种典型的癌症易感疾病，通常与p53肿瘤抑制基因的种系突变相关。对广泛的成人和儿童癌症谱以及p53突变分布的研究，加深了人们对癌症基因型-表型相关性的理解。然而，仅通过识别受影响个体中的种系p53突变，并不容易解释复杂的LFS表型。最近的研究发现了一些修饰LFS表型的遗传事件。这些事件包括基因内多态性、p53调节途径中基因的突变/多态性，以及更广泛的事件，如异常拷贝数变异和端粒损耗。这些遗传事件可能部分解释了LFS家族内部和之间肿瘤组织类型的广度、家族内明显提前的发病年龄，以及受影响家庭成员之间的临床结局范围。本综述将探讨LFS的临床和遗传学定义，并深入了解从对这种罕见疾病的研究中获得的经验教训如何为其他家族性癌症综合征中的类似问题提供参考。
