BENZO[A]PYRENE-INDUCED MURINE SKIN TUMORS EXHIBIT FREQUENT AND CHARACTERISTIC G-TO-T MUTATIONS IN THE P53-GENE
BENZO[A]PYRENE-INDUCED MURINE SKIN TUMORS EXHIBIT FREQUENT AND CHARACTERISTIC G-TO-T MUTATIONS IN THE P53-GENE
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DOI：
10.1073/pnas.90.3.1013
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发表时间：
1993-02-01
影响因子：
11.1
通讯作者：
KLEINSZANTO, AJP
中科院分区：
文献类型：
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作者：
RUGGERI, B;DIRADO, M;KLEINSZANTO, AJP
人类烟草相关癌症在 p53 肿瘤抑制基因的突变热点区域表现出高频率的 G 到 T 颠换，这可能是烟草烟雾中特定诱变剂的结果，尤其是苯并[a]芘 (B[a]P)。然而，尚未使用 B[a]P 诱导的肿瘤发生的体内动物模型来通过实验证实这些分子流行病学数据。在使用 B[a]P 的完整致癌方案诱导的 20 个皮肤肿瘤中，对鼠 p53 的热点区域（包括外显子 5-8）进行了直接 DNA 序列分析。序列分析揭示了癌症中的许多杂合错义突变，特别是在 p53 基因的外显子 7 和 8 中，并且专门针对鸟嘌呤残基。此外，70% (5/7) 的特征突变是 G 到 T 的颠换。相比之下，在完整的致癌方案或两阶段的致癌方案中，对 7,12-二甲基苯并[a]蒽 (DMBA) 诱导的 36 个皮肤肿瘤进行直接 DNA 序列分析，结果显示杂合 p53 突变的频率为 30%，大多数突变在癌中发现，但只有一个 G 到 T 颠换 (1/8)。因此，虽然突变频率相似，但 B[a]P 诱导的皮肤肿瘤中 p53 突变的模式和类型与 DMBA 诱导的鳞状肿瘤中的突变谱显着不同。 B[a]P 诱导肿瘤的这些体内发现为体外和分子流行病学证据提供了支持，表明 p53 肿瘤抑制基因可能是与人类烟草相关癌症病因学相关的代谢激活 B[a]P 物种的选择性靶标。
Human tobacco-related cancers exhibit a high frequency of G to T transversions in the mutation hot spot region of the p53 tumor suppressor gene, possibly the result of specific mutagens in tobacco smoke, most notably benzo[a]pyrene (B[a]P). No in vivo animal model of B[a]P-induced tumorigenesis has been used, however, to substantiate these molecular epidemiological data experimentally. Direct DNA sequence analysis of the hot spot region (exons 5-8 inclusive) of murine p53 was performed in 20 skin tumors induced by a complete carcinogenesis protocol with B[a]P. Sequence analyses revealed numerous heterozygous missense mutations in carcinomas, specifically in exons 7 and 8 of the p53 gene, and targeting exclusively guanine residues. Moreover, 70 % (5/7) of the mutations characterized were G to T transversions. In contrast, direct DNA sequence analysis of 36 skin tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) in either a complete carcinogenesis protocol or in a two-stage carcinogenesis protocol revealed a 30% frequency of heterozygous p53 mutations, with the majority of mutations found in carcinomas, but only a single G to T transversion (1/8). Thus, while mutation frequencies are similar, the pattern and type of p53 mutations in B[a]P-induced skin tumors differs significantly from the mutation spectra in DMBA-induced squamous neoplasias. These in vivo findings in B[a]P-induced tumors lend support to in vitro and molecular epidemiological evidence, suggesting that the p53 tumor suppressor gene may be a selective target of metabolically activated B[a]P species etiologically associated with human tobacco-related cancers.