Chromosome instability is a predominant trait of fibroblasts from Li-Fraumeni families.
Chromosome instability is a predominant trait of fibroblasts from Li-Fraumeni families.
复制标题
DOI：
10.1038/bjc.1998.364
复制
发表时间：
1998-06
影响因子：
8.8
通讯作者：
Scott, D
中科院分区：
文献类型：
--
作者：
Boyle, J M;Mitchell, E L;Greaves, M J;Roberts, S A;Tricker, K;Burt, E;Varley, J M;Birch, J M;Scott, D
先前的工作表明 p53 在细胞周期控制、基因组稳定性和细胞对 DNA 损伤剂的反应中发挥作用。然而，关于 TP53 中确定的种系突变杂合的人成纤维细胞的数据很少。我们报告了对来自 12 个李法美尼综合征 (LFS) 家族的 25 株菌株和来自正常志愿者的 18 株菌株的研究。这些家族包括三个经典的 LFS 家族，但未发现 TP53 突变。在携带突变的家族中，寿命延长和对低剂量率电离辐射的抵抗力与 TP53 突变的存在存在统计学上显着的相关性。然而，并非所有杂合子的寿命都增加或具有放射抗性，并且来自没有 TP53 突变的 LFS 家族受癌症影响的成员的成纤维细胞在这两个终点中都没有表现出显着增加。相比之下，所有携带突变的菌株都显示出基因组不稳定的证据，表现为非整倍性，并且在高达 100% 的细胞中积累了结构性染色体畸变，通常伴随着野生型 TP53 等位基因的丢失，就在衰老之前。在没有 TP53 突变的家族的成纤维细胞中也观察到了高于正常细胞的非整倍性水平，这表明染色体不稳定性是决定这些家族癌症倾向的主要因素。
Previous work has indicated a role for p53 in cell cycle control, genomic stability and cellular responses to DNA-damaging agents. However, few data are available for human fibroblasts heterozygous for defined germline mutations in TP53. We report studies on 25 strains derived from 12 families with Li-Fraumeni syndrome (LFS) and 18 strains from normal volunteers. The families include three that are classical LFS families, but in whom no TP53 mutation has been found. In the families with mutations, increased longevity and resistance to low-dose-rate ionizing radiation showed a statistically significant association with the presence of TP53 mutations. However, not all heterozygotes had increased longevity or were radioresistant, and fibroblasts from cancer-affected members of LFS families without TP53 mutations showed no significant increase in either of these end points. In contrast, all mutation-carrying strains showed evidence of genomic instability, expressed as aneuploidy, and accumulated structural chromosome aberrations in up to 100% of cells, usually accompanied by loss of the wild-type TP53 allele, immediately before senescence. Levels of aneuploidy higher than in normal cells were also observed in fibroblasts from families without TP53 mutations, suggesting that chromosome instability is a major factor in determining the cancer proneness of these families.