TUMOR SUPPRESSION GENES IN HUMAN CARCINOGENESIS

p53肿瘤抑制基因非常适合于突变分析。 这是因为：a）它是最常见的遗传病变 在人类癌症中，B）其作为分子靶标的合理大小，和 c）它可以指示具有病理生物学特性的突变的选择 意义 p53突变谱在不同的癌症中是不同的。 结肠、肺、食管、乳腺、肝、脑、网状内皮组织 和造血组织。 对这些突变的分析可以提供线索 这些不同肿瘤的病因学和特异性肿瘤的功能， p53的区域。 转变主要发生在结肠、脑和淋巴 恶性肿瘤。 密码子175中CpG二核苷酸的突变热点， 245、248、273和282可能反映了内源性诱变机制，例如， 5-甲基胞嘧啶脱氨为胸苷。 氧自由基包括 一氧化氮可提高脱氨速率。 G：C到T：A 颠换是在癌症中观察到的最常见的置换， 肺、乳房、食道和肝脏，最有可能是由于 庞大的致癌物-DNA加合物。 G到T颠换在肺中更常见 吸烟者的癌症与从不吸烟者相比。 高频 非转录DNA链中的p53突变反映了 链特异性修复。 p53突变通常也表明 预后 在B型肝炎病毒（HBV）和 黄曲霉毒素B1是癌症的危险因素，大多数突变都在第三位， 密码子249的核苷酸对。 在B型肝炎和 C病毒-而不是黄曲霉毒素B1-是危险因素，p53突变是 分布在许多密码子中。 HBV X蛋白与p53复合物 蛋白质并抑制其序列特异性DNA结合， 反式激活能力 p53的反式激活功能也可能 由其氧化还原状态调节。 诱导皮肤癌的实验研究 紫外线是由p53突变的发生指示的， 二嘧啶位点包括CC到TT双碱基变化。 总的来说， 人类癌症类型之间突变谱的这些差异表明， 内外因病因 人类致癌作用和进一步研究的假设。

The p53 tumor suppressor gene is well suited for analysis of mutational spectrum in human cancers because: a) it's the most common genetic lesion in human cancers, b) of its reasonable size as a molecular target, and c) it may indicate selection of mutations with pathobiological significance. The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues and hemopoietic tissues. Analysis of these mutations can provide clues to the etiology of these diverse tumors and to the function of specific regions of p53. Transitions predominate in colon, brain and lymphoid malignancies. Mutational hotspots at CpG dinucleotides in codons 175, 245, 248, 273 and 282 may reflect endogenous mutagenic mechanisms, e.g., deamination of 5-methylcytosine to thymidine. Oxy-radicals including nitric oxide may enhance the rate of deamination. G:C to T:A transversions are the most frequent substitutions observed in cancers of the lung, breast, esophagus and liver, and are most likely to be due to bulky carcinogen-DNA adducts. G to T transversion is more common in lung cancers from smokers when compared to never smokers. The high frequency of p53 mutations in the nontranscribed DNA strand is a reflection of strand specific repair. p53 mutation also generally indicates a poor prognosis. In geographic areas where hepatitis B virus (HBV) and aflatoxin B1 are cancer risk factors, most mutations are at the third nucleotide pair of codon 249. In geographic areas where hepatitis B and C viruses-but not aflatoxin B1-are risk factors, the p53 mutations are distributed in numerous codons. HBV X protein complexes with the p53 protein and inhibits its sequence specific DNA binding and transactivating capacity. The transactivating function of p53 also may be modulated by its redox state. The induction of skin carcinoma by ultraviolet light is indicated by the occurrence of p53 mutations at dipyrimidine sites including CC to TT double base changes. In summary, these differences in mutational spectrum among human cancer types suggest the etiological contributions in both exogenous and endogenous factors to human carcinogenesis and hypotheses for further investigation.