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首页> 外文会议>Cold Spring Harbor Symposium on Quantitative Biology >The Evolution of Tumors in Mice and Humans with Germline p53 Mutations
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The Evolution of Tumors in Mice and Humans with Germline p53 Mutations

机译：用种系P53突变对小鼠和人类肿瘤的演变

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Mice with a homozygous p53 gene deletion develop thymic lymphomas by 9 wk of age. Using the sequence of the rearranged T-cell receptor gene from each clone of cells in the thymus, one can determine the number of independent transformation events. These tumors are oligoclonal, occurring at a frequency of 0.13-0.8 new cancer clones per day. By 20 wk only a few clones are detected, indicating competition among transformed cell clones. DNA sequencing of these tumors demonstrates a point mutation frequency of one per megabase and many genes that are consistently amplified or deleted in independent tumors. The tumors begin with an inherited p53 gene deletion. Next is a PTEN mutation in a stem cell or progenitor cell, before the rearrangement of the T-cell receptor. After that, the T-cell clone selects gene amplifications in cyclin D and cdk-6, and in Ikaros in the Notch pathway. Humans heterozygous for the p53 mutant gene in the germline (Li-Fraumeni syndrome) develop cancers at an early age. The penetrance of heterozygous p53 mutations is ~93% of individuals developing tumors over their lives. At older ages the remaining 7% of this Li-Fraumeni population actually have a lower risk of developing tumors than the population at large with wild-type p53 genes.
机译：用纯合P53基因缺失的小鼠发育胸腺淋巴瘤9周龄。使用从胸腺中的每个克隆的重排型T细胞受体基因的序列，可以确定独立变换事件的数量。这些肿瘤是寡核，以0.13-0.8新的癌症克隆的频率发生。 20 WK只检测到几个克隆，表明转化细胞克隆之间的竞争。这些肿瘤的DNA测序证明了每兆糖的点突变频率和许多在独立肿瘤中持续放大或缺失的许多基因。肿瘤从遗传的P53基因缺失开始。接下来是干细胞或祖细胞中的PTEN突变，在T细胞受体重新排列之前。之后，T细胞克隆在Cyclin D和CDK-6中选择基因扩增，并且在凹口途径中的Ikaros。人体杂合在种系中的p53突变基因（Li-Fraumeni综合征）在休眠中发育癌症。杂合P53突变的渗透率为〜93％的个体在其生命中发育肿瘤。在年龄较大的年龄均为李 - 弗拉梅尼人群的剩余7％实际上具有较低的肿瘤风险，而不是野生型P53基因的群体。

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