Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53
Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53
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DOI：
10.1126/science.274.5286.430
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发表时间：
1996-10-18
期刊：
影响因子：
56.9
通讯作者：
Pfeifer, GP
中科院分区：
文献类型：
--
作者：
Denissenko, MF;Pao, A;Pfeifer, GP
香烟烟雾中的致癌物质，如苯并[a]芘，与肺癌的发生有关。在核苷酸分辨率下绘制了苯并[a]芘二醇环氧化物(BPDE)加合物沿p53基因外显子在HeLa细胞和支气管上皮细胞中的分布。在密码子157、248和273的鸟嘌呤位置有强烈和选择性的加合物形成。这些相同的位置是人类肺癌的主要突变热点。因此，靶向加合物的形成而不是表型选择似乎塑造了肺癌中的p53突变谱。这些结果提供了一种明确的化学致癌物和人类癌症之间的直接病因学联系。
Cigarette smoke carcinogens such as benzo[a]pyrene are implicated in the development of lung cancer. The distribution of benzo[a]pyrene diol epoxide (BPDE) adducts along exons of the P53 gene in BPDE-treated HeLa cells and bronchial epithelial cells was mapped at nucleotide resolution. Strong and selective adduct formation occurred at guanine positions in codons 157, 248, and 273. These same positions are the major mutational hotspots in human lung cancers. Thus, targeted adduct formation rather than phenotypic selection appears to shape the P53 mutational spectrum in lung cancer. These results provide a direct etiological link between a defined chemical carcinogen and human cancer.