分子流行病学富有挑战性的目标是通过接触致癌物的定量分析和人体易感性的遗传分析来确定个体患肿瘤的风险和几率。肿瘤抑制基因突变谱的分子考古学发现产生了关于人类肿瘤分子发病机理和病因的假设。质谱检查发现体细胞（p53基因）突变显示：环境致癌物（例如：黄曲霉素B1）和内生性物质（例如：氧自由基）与人类肝癌的病因学关联。p53突变细胞的数量（即：p53突变负荷）在以下几种非肿瘤患者体内明显升高：慢性病毒性肝炎患者、饮食习惯与黄曲霉素B1紧密相关的患者、血色病患者（氧自由基负荷过大）。细胞压力增大会激活p53基因从而影响包括细胞周期检控点、DNA修复、细胞凋亡和衰老等在内的代谢过程。体细胞p53位点的突变会降低机体应对细胞压力的保护性反应。病毒癌基因蛋白也可以影响p53的反应通路。例如，乙型肝炎病毒X protein可以结合到p53的C端，从而抑制p53介导的转录－转激活和凋亡，进而削弱核苷酸切割修补（NER）。我们同时进行了p53调控的基因转录凋亡功能的研究。通过微阵列DNA损伤细胞表达分析，研究人员发现了新的p53靶基因。例如，凋亡蛋白酶活化因子-1（APAF1）和锰超氧化物歧化酶（Mn SOD2）被位于基因组转录起始点（内有p53反应单元）上游的p53转录激活。APAF1是凋亡体（一种蛋白复合物）中的一种重要的蛋白质。SOD2的上调可以致使抗氧化酶的失衡，从而导致过氧化氢（氧化压力）的增加。总之，p53是几条细胞压力调节通路上的关键点。瘤前病变和肿瘤p53突变的结构和功能分析可以用于肿瘤病因学和分子发病机理的研究中。
p53 tumor suppressor network: at the crossroads of the molecular carcinogenesis and
molecular epidemiology of liver cancer
S.P. HUSSAIN, A.I. ROBLES, X.W. WANG, P.R. GALLE 1 , Z.T. SUN 2 , C.C. HARRIS
Laboratory of Human Carcinogenesis, NCI, NIH, Bethesda, MD 20892 USA; 1 Dept. of Internal Med., Johannes Gutenberg-Universitat, Mainz, Germany; 2 Dept. of Molecular Immunology, Cancer Institute, Chinese Academy of Medical Science, Panjiayuan, Beijing 100021, China The challenging goal of molecular epidemiology is to identify individuals at high cancer risk by quantitative assessment of carcinogen exposure and genetic analysis of host susceptibility factors. The molecular archaeology of the mutation spectra of tumor suppressor genes generates hypotheses concerning the etiology and molecular pathogenesis of human cancer. The spectrum of somatic mutations in the p53 gene implicates environmental carcinogens, e.g., aflatoxin B1 and endogenous agents, e.g., oxyradicals, in the etiology of human liver cancer. The frequency of p53 mutant cells, i.e., the p53 mutation load, is increased in nontumorous liver from individuals with either chronic viral hepatitis and dietary exposure to aflatoxin B1, or oxyradical overload due to hemochromatosis. Cellular stress activates the p53-response pathway involving cell cycle checkpoints, DNA repair, apoptosis, and senescence. Somatic mutations in p53 attenuate this protective response to cellular stress. Viral oncoproteins can also target the p53 response pathway. For example, the hepatitis B virus X protein also binds to the C-terminus of p53, inhibits p53-mediated transcription-transactivation and apoptosis, and attenuates nucleotide excision repair (NER). We are also investigating the apoptotic functions of genes transcriptionally regulated by p53. Novel p53 target genes have been identified by microarray expression analysis of DNA-damaged cells. For example, apoptotic protease activating factor-1 (APAF1) and Mn superoxide dismutase (SOD2) are transcriptionally transactivated by p53 binding to genomic sequences upstream from the transcription start sites that contain a classical p53-response element. APAF1 is an essential protein in the apoptosome. Upregulation of SOD2 can cause an imbalance in antioxidant enzymes, an increase in hydrogen peroxide, and oxidative stress. In summary, p53 is at the crossroads of several response pathways to cellular stress. The structural and functional analysis of p53 mutations in preneoplastic lesions and tumors provides insight into the etiology and molecular pathogenesis of human cancer.
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