Relationship between UV-induced mutant p53 patches and skin tumours, analysed by mutation spectra and by induction kinetics in various DNA-repair-deficient mice
Relationship between UV-induced mutant p53 patches and skin tumours, analysed by mutation spectra and by induction kinetics in various DNA-repair-deficient mice
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DOI：
10.1093/carcin/bgi198
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发表时间：
2005-12-01
期刊：
影响因子：
4.7
通讯作者：
de Gruijl, FR
中科院分区：
文献类型：
--
作者：
Rebel, H;Kram, N;de Gruijl, FR
p53 免疫阳性表皮角质形成细胞簇（所谓的 p53 斑块、克隆或病灶）存在于阳光或紫外线 (UV) 暴露的皮肤中。我们研究了这些 p53 斑块在多大程度上是长期受辐射的无毛 (SKH1) 小鼠皮肤癌的真正前兆。因此，比较了激光显微切割突变 p53 斑块和癌的 p53 基因外显子 5-8 的突变谱。我们发现的突变主要是位于已知热点的 UV 特征突变（二嘧啶位点处的 C -> T 和 CC -> TT）。两个光谱之间没有发现显着差异，这表明所有 p53 斑块都含有可能进展为癌症的突变。为了检查这些p53斑块是否可以用作肿瘤风险指标，我们对具有各种核苷酸切除修复（NER）缺陷的转基因小鼠（即着色性干皮病A（Xpa）、Xpc和科凯恩综合征B（Csb）和野生型小鼠）中这些斑块和癌症的诱导动力学进行了广泛的比较。按照上述顺序，小鼠品系在每天暴露于 40 J/m(2) 紫外线的过程中同时产生 p53 斑块和癌。因此，NER缺陷小鼠产生斑块的顺序可以预测它们产生肿瘤的顺序。 Xpc 缺陷小鼠的斑块诱导动力学与其他小鼠显着不同：有一个稳定期（第 13-41 天），其中每只小鼠的斑块数量仅限于 5-10 个，然后与其他组平行出现爆炸性增加。 p53 斑块进展为癌症的几率相对较小（当第一个肿瘤出现时，估计为 8300-40 000 分之一/个体），但我们的结果强烈表明 p53 斑块与癌症之间存在因果关系。
Clusters of p53 immunopositive epidermal keratinocytes (so-called p53 patches, clones or foci) are found in sun or ultraviolet (UV) light-exposed skin. We investigated to what extent these p53 patches are genuine precursors of skin carcinomas in chronically irradiated hairless (SKH1) mice. The mutation spectra of exons 5-8 of the p53 gene of laser-micro-dissected mutant p53 patches and carcinomas were therefore compared. The mutations we found were mainly UV-signature mutations (C -> T and CC -> TT at dipyrimidine sites) located at known hotspots. No significant differences were found between both spectra, indicating that all p53 patches harbour mutations with which they could progress to carcinomas. To examine whether these p53 patches can be used as tumour risk indicators, we made an extensive comparison of the induction kinetics of these patches and carcinomas in genetically modified mice with various defects in nucleotide excision repair (NER), i.e. xeroderma pigmentosum A (Xpa), Xpc and Cockayne syndrome B (Csb) and wild-type mice. In this aforementioned order, the mouse strains developed both p53 patches and carcinomas in the course of daily exposure to 40 J/m(2) UV. Hence, the order in which the NER-deficient mice developed patches was predictive of the order in which they developed tumours. The induction kinetics of the patches in Xpc-deficient mice differed notably from the others: there was a stationary phase (days 13-41) where the numbers were limited to 5-10 patches per mouse before an explosive increase which ran parallel to the other groups. The chance that a p53 patch progresses to carcinoma is relatively small (estimated at 1 out of 8300-40 000/individual when the first tumour appears), but our results are strongly indicative of a causal relationship between p53 patches and carcinomas.