p53 gene mutation pattern in rat liver tumors induced by vinyl chloride.
p53 gene mutation pattern in rat liver tumors induced by vinyl chloride.
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发表时间：
1997-05
期刊：
影响因子：
11.2
通讯作者：
A. Barbin;O. Froment;S. Boivin;M. Marion;F. Belpoggi;C. Maltoni;R. Montesano
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作者：
A. Barbin;O. Froment;S. Boivin;M. Marion;F. Belpoggi;C. Maltoni;R. Montesano
氯乙烯 (VC) 会诱发人类和啮齿类动物的肝脏血管肉瘤 (ASL) 和肝细胞癌 (HCC)。我们检查了 Sprague Dawley 大鼠中 VC 诱导的 ASL 和 HCC 中是否存在 p53 基因突变；使用 PCR 扩增、单链构象多态性分析和直接 DNA 测序，分析了 25 个 ASL 和 8 个 HCC 外显子 5-8 的点突变。在 11 例 (44%) 的 ASL 和 1 例 HCC 中发现了突变。在一个肿瘤中发现了 12 个碱基对缺失；所有其他都是碱基对替换。在 A:T 碱基对处观察到了 9 个点突变（5 个 A:T --> T:A、2 个 A:T --> G:C 和 2 个 A:T --> C:G），并且在 3 个 G:C --> A:T 转换中，只有一个位于 CpG 位点。在 ASL 中，在外显子 5 中发现了 4 个突变，在外显子 6 中发现了 2 个突变，在外显子 7 中发现了 6 个突变；一种 HCC 中发现的碱基对替换位于外显子 8 中。一种 ASL 表现出两个点突变，其中包括一个沉默点突变。两个 ASL 在密码子 203 中表现出相同的突变，另外两个样本在密码子 253 中表现出相同的突变。发现在三个 ASL 中密码子 235 发生突变。这些数据表明，在大鼠中由 VC 诱导的 ASL 中，p53 经常发生突变，并且正如在暴露于 VC 的人类 ASL 中观察到的那样，大多数错义突变涉及 A:T 碱基对。发现的突变特征模式表明，两个物种中 VC 诱导的 p53 突变存在共同机制，并且这些突变与肝脏中 VC 形成的 DNA 乙烯加合物一致。在两只大鼠 ASL 的密码子 253 的第一个核苷酸中观察到的 A:T --> T:A 颠换相当于之前在与 VC 暴露相关的一个人 ASL 的密码子 255 中观察到的 A:T --> T:A 颠换。
Vinyl chloride (VC) induces angiosarcomas of the liver (ASL) and hepatocellular carcinomas (HCCs) in humans and rodents. We examined the presence of p53 gene mutations in ASL and HCC induced by VC in Sprague Dawley rats; 25 ASL and eight HCCs were analyzed for point mutations in exons 5-8, using PCR amplification, single-strand conformation polymorphism analysis, and direct DNA sequencing. Mutations were found in 11 (44%) of the ASL and in 1 HCC. A 12-base pair deletion was found in one tumor; all others were base pair substitutions. Nine of the point mutations were observed at A:T base pairs (5 A:T --> T:A; 2 A:T --> G:C, and 2 A:T --> C:G), and of three G:C --> A:T transitions, only one was at a CpG site. In ASL, four mutations were found in exon 5, two in exon 6, and six in exon 7; the base pair substitution found in one HCC was in exon 8. One ASL exhibited two point mutations, including a silent one. Two ASL exhibited the same mutation in codon 203 and two other samples in codon 253. Codon 235 was found to be mutated in three ASL. These data show that p53 is often mutated in ASL induced by VC in rats and, as observed in ASL in humans exposed to VC, the majority of the missense mutations involved A:T base pairs. The characteristic patterns of mutations found suggest that a common mechanism operates in VC-induced p53 mutagenesis in both species, and these mutations are consistent with the formation of DNA etheno adducts by VC in the liver. The A:T --> T:A transversion observed in the first nucleotide of codon 253 in two rat ASL is equivalent to the A:T --> T:A transversion characterized previously in codon 255 in one human ASL associated with VC exposure.