ANALYSIS OF GENETIC ALTERATIONS DURING HEPATOCARCINOGENESIS

肝癌发生过程中的基因改变分析

• 批准号: 3774876
• 负责人: S S THORGEIRSSON
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3774876
• 关键词: China; Macaca fascicularis; aflatoxins; chemical carcinogen; chemical carcinogenesis; chemical related neoplasm /cancer; chromosomes; complementary DNA; geographic site; hepatitis B virus group; hepatocellular carcinoma; human genetic material tag; laboratory rat; loss of heterozygosity; messenger RNA; mutagens; neoplasm /cancer genetics; nutrition related neoplasm /cancer; nutrition related tag; point mutation; polymerase chain reaction; restriction fragment length polymorphism; tumor suppressor genes; virus related neoplasm /cancer

Mutations in the putative p53 tumor suppressor gene and loss of heterozygosity (LOH) at several chromosomal sites in a tumor indicates that inactivation of several tumor suppressor genes are necessary for development of the tumor. Aflatoxin B1 has been suggested as a causative agent for a G to T mutation at codon 249 in the p53 tumor suppressor gene in human hepatocellular carcinomas (HCCs) from southern Africa and Qidong in China. It seems to be important to examine whether the causative agent for the selective p53 mutation also is involved in other tumor suppressor genes. To clarify the involvement of aflatoxin B1 in HCCs in China, we examined the p53 gene for mutations and LOH on the p53, retinoblastoma (Rb) and adenomatis polyposis coli (APC) genes, and chromosomes 4, 13, and 16 using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis, as well as restriction fragment length polymorphism (RFLP) analysis. HCCs were examined from two different areas of China: Qidong, where exposure to hepatitis B virus (HBV) and aflatoxin B1 is high; and Beijing, where exposure to HBV is high but aflatoxin B1 is low. Frequencies of mutation, loss, and aberration (mutation and loss) of the p53 gene in 25 HCCs from Qidong were 60, 58, and 80%, respectively. The frequencies in 9 HCCs from Beijing were almost the same, being 56, 57, and 78%, respectively. However, the frequencies of a G to T transversion at codon 249 in HCCs from Qidong were 52% versus 0% for Beijing. Loss of the Rb and APC genes were observed in 44% and 7%, respectively, of HCCs from Qidong. LOH on chromosome 4 and 16 was relatively frequent in HCCs from Qidong, but rare in HCCs from Beijing. LOH on chromosome 13 was frequent in both Qidong and Beijing. These data suggest that aflatoxin-B1 might be one of the causative agents for a G to T transversion at codon 249 of the p53 gene in Qidong, but other factors might be involved in the development of HCCs in Beijing. Therefore, although the p53 gene plays a critical role in the development of HCCs, distinct mechanisms appear to be responsible for human hepatocarcinogenesis in different geographic areas.

假定的p53肿瘤抑制基因的突变和 肿瘤中几个染色体位点的杂合性（洛）表明 几种肿瘤抑制基因的失活是必要的， 肿瘤的发展。 黄曲霉毒素B1被认为是 针对p53肿瘤抑制基因中密码子249处G至T突变的药剂 在来自南部非洲和启东的人肝细胞癌（HCC）中， 在中国 重要的是要检查病原体是否 因为选择性p53突变也参与了其他肿瘤抑制因子的表达， 基因. 为了阐明黄曲霉毒素B1与中国肝癌的关系，我们 检查了p53基因的突变和p53上的洛缺失，视网膜母细胞瘤 (Rb)和大肠腺瘤息肉病（APC）基因，以及染色体4，13， 聚合酶链反应-单链构象多态性 （PCR-SSCP）分析，以及限制性片段长度多态性 （RFLP）分析。 对来自中国两个不同地区的HCC进行了检查： 启东，那里暴露于B型肝炎病毒（HBV）和黄曲霉毒素B1， 高;北京，那里的乙肝病毒暴露率高，但黄曲霉毒素B1低。 基因突变、缺失和畸变（突变和缺失）的频率 启东地区25例HCC中p53基因阳性率分别为60%、58%和80%。 的 北京地区9例HCC中的频率基本相同，分别为56，57， 分别为78%。 然而，G到T颠换的频率在 249密码子在启东肝癌中的阳性率为52%，而在北京肝癌中为0%。 损失 Rb和APC基因分别在44%和7%的HCC中被观察到， 启东。 4号和16号染色体上的洛缺失在肝癌中相对常见， 启东地区的肝癌发病率较高，而北京地区的肝癌发病率较低。 13号染色体上的洛缺失频率较高 在启东和北京。 这些数据表明，黄曲霉毒素B1可能是 其中一个致病因子在密码子249的G到T颠换， p53基因在启东地区的发生发展中起重要作用，但可能有其他因素参与 北京的HCC 因此，尽管p53基因在肿瘤的发生中起着关键作用， 在HCC发展中的作用，不同的机制似乎是 在不同的地理区域负责人类肝癌的发生。