Somatic mutations in the D-loop and decrease in the copy number of mitochondrial DNA in human hepatocellular carcinoma
Somatic mutations in the D-loop and decrease in the copy number of mitochondrial DNA in human hepatocellular carcinoma
复制标题
DOI：
10.1016/j.mrfmmm.2003.12.011
复制
发表时间：
2004-03-22
影响因子：
2.3
通讯作者：
Wei, YH
中科院分区：
文献类型：
--
作者：
Lee, HC;Li, SH;Wei, YH
线粒体DNA（mtDNA）的体细胞突变已在许多人类癌症中检测到，包括肝细胞癌（HCC）。发现D-loop区是肿瘤mtDNA突变的“热点”。然而，在肿瘤组织中的mtDNA的拷贝数的D-环突变的影响知之甚少。采用直接测序法，我们检测了61例HCC和相应的非肿瘤肝组织中mtDNA D环区的突变。结果表明，39.3%的肝癌细胞线粒体DNA D环区存在体细胞突变，且多为同质突变。其中37.0%（10/27）的突变为T → C和G → A的转换，40.7%（11/27）的突变位于线粒体DNA第303和309位核苷酸之间的多胞苷段。此外，我们发现60.5%的肝癌患者mtDNA拷贝数显著降低，尤其是在mtDNA D环体细胞突变的患者中（17/24）。mtDNA拷贝数的减少与mtDNA重链复制起点附近的点突变密切相关。有趣的是，我们发现42.9%（6/14）的肝癌没有D环突变，线粒体DNA拷贝数减少，表明其他未知的因素参与线粒体生物合成可能是缺陷的肿瘤。在这项研究中获得的结果强烈表明，体细胞突变的D-环连同mtDNA拷贝数的减少可能是一个重要的事件在早期阶段的肝癌发生。(C)2004 Elsevier B. V.保留所有权利。
Somatic mutations in mitochondrial DNA (mtDNA) have been detected in many human cancers, including hepatocellular carcinoma (HCC). The D-loop region was found to be a "hot spot" for mutation in mtDNA of the tumors. However, effects of the D-loop mutations on the copy number of mtDNA in tumor tissues are poorly understood. Using direct sequencing, we examined mutations in the D-loop region of mtDNA in 61 HCCs and the corresponding non-tumor liver tissues. The results revealed that 39.3% of the HCCs carried somatic mutation(s) in the D-loop of mtDNA, and most of these mutations were homoplasmic. Moreover, 37.0% (10/27) of these mutations were T-to-C and G-to-A transitions and 40.7% (11/27) of them were located in the polycytidine stretch between nucleotide position (np) 303 and 309 of mtDNA. In addition, we found that mtDNA copy number of HCC was significantly decreased in 60.5% of the patients with hepatoma, especially in those with somatic mutation(s) in the D-loop of mtDNA (17/24). This decrease in mtDNA copy number was highly associated with the occurrence of point mutations near the replication origin of the heavy-strand of mtDNA. Interestingly, we found that 42.9% (6/14) of the HCCs without mutation in the D-loop had a reduced copy number of mtDNA, indicating that other unidentified factors involved in mitochondrial biogenesis might be defective in the tumor. The results obtained in this study strongly suggest that somatic mutations in the D-loop together with the decrease in the copy number of mtDNA may be an important event during the early phase of liver carcinogenesis. (C) 2004 Elsevier B.V. All rights reserved.