Hussain S P, Harris C C
Laboratory of Human Carcinogenesis, Building 37, Room 2C05, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Mutat Res. 2000 Apr;462(2-3):311-22. doi: 10.1016/s1383-5742(00)00015-6.
Mutations of the p53 tumor suppressor gene are found in about 50% of all human cancers. The p53 mutation spectra in these cancers are providing clues to the etiology and molecular pathogenesis of cancer. Recent studies indicate that the p53 protein is involved in several vital cellular functions, such as gene transcription, DNA synthesis and repair, cell cycle arrest, senescence and programmed cell death. Mutations in the p53 gene can abrogate these functions and may contribute to genomic instability and progression to cancer. Characteristic p53 mutation spectra have been associated with dietary aflatoxin B(1) (AFB(1)) exposure and hepatocellular carcinoma (HCC); sunlight exposure and skin cancer; and cigarette smoking and lung cancer. The mutation spectrum also reveals those p53 mutants that provide cells with a selective clonal expansion advantage during the multistep process of carcinogenesis. Although a number of different exogenous carcinogens have been shown to selectively target p53, pieces of evidence supporting the endogenous insult of p53 are accumulating. Furthermore, analysis of a characteristic p53 mutation load in nontumorous human tissue can indicate previous carcinogen exposure and may identify individuals at an increased cancer risk.
在大约50%的人类癌症中都发现了p53肿瘤抑制基因的突变。这些癌症中的p53突变谱为癌症的病因学和分子发病机制提供了线索。最近的研究表明，p53蛋白参与多种重要的细胞功能，如基因转录、DNA合成与修复、细胞周期停滞、衰老和程序性细胞死亡。p53基因的突变可消除这些功能，并可能导致基因组不稳定和癌症进展。特征性的p53突变谱与饮食中黄曲霉毒素B1（AFB1）暴露及肝细胞癌（HCC）、阳光暴露及皮肤癌、吸烟及肺癌有关。突变谱还揭示了那些在癌症发生的多步骤过程中为细胞提供选择性克隆扩增优势的p53突变体。虽然已证明多种不同的外源性致癌物可选择性地靶向p53，但支持p53内源性损伤的证据也在不断积累。此外，分析非肿瘤性人类组织中特征性的p53突变负荷可表明既往致癌物暴露情况，并可能识别出癌症风险增加的个体。
