人类肿瘤组织线粒体基因长度不稳定在肿瘤发生学上的角色(英文)

Influence of instability of mitochondrial genome length on tumorigenesis in human tumors

背景:错配修复基因缺陷和微卫星不稳定是在多种人类肿瘤中被证实存在的两个遗传性变异,虽然目前已有研究阐明肿瘤细胞的线粒体基因具有广泛的变异谱,但较少有研究注意线粒体基因长度的不稳定。目的:探讨不同肿瘤组织中线粒体基因长度不稳定状态和在肿瘤发生中可能的作用。设计:以诊断为依据设立对照的实验研究。地点和对象:实验在解放军总医院老年心血管病研究所完成,对象为配对肿瘤和周围组织外科切除后保存的样本,所有样本均来自台湾彰化基督教医院和美国乔治城大学医学中心。干预:抽提143例患者的5种肿瘤组织及配对的正常组织的DNA,利用32对重叠引物扩增全部线粒体基因,来自肿瘤和相应正常组织的DNA片段进行配对分析。时相温度梯度凝胶电泳法进行突变筛查。如发现肿瘤与相应正常组织的DNA片段电泳条带呈现差异则进行测序以明确短片段的插入和缺失突变,PCR检测有样本常见的大范围缺失突变。主要观察指标:不同肿瘤组织中线粒体DNA缺失与插入情况。结果:在全部5种类型的肿瘤中均发现有短片段的缺失和插入突变,肺癌和口腔癌此类突变的发生率高于其他类型肿瘤。除肝癌外,在部分肿瘤及其相应的正常组织中可检测到低水平的线粒体常见大范围缺失突变,发生率约5%～40%。

BACKGROUND:The mismatch repair gene(MMR) defects and microsatellite instability(MSI) are two genetic alterations that have been documented in a wide variety of human cancers.Although a wide spectrum of alteration in mtDNA of cancer cells have been established,little attention has been paid to mitochondrial DNA length instability. OBJECTIVE:To explore the status of mitochondrial genome length instability in different tumors and its possible role in the tumorigenesis. DESIGN:A case controlled experimental study based on diagnosis was conducted. SETTING and PARTICIPANTS:Paired tumor and surrounding tissues were previously banked specimens which were surgically removed and histologically confirmed from patients with 73 breast(73 cases),18 lung(18),20 esophageal(20),18 oral(18) and 20 liver(20) cancers.All samples came from Changhua Christian Hospital of Taiwan and Georgetown University Medical Center of USA. MAIN OUTCOME MEASURES:Deletions and insertions of mtDNA from different cancer tissues. RESULTS:The short deletion and insertion were been found in all types of tumors.Lung and oral cancer showed higher incidence of those mutations than the others.Except liver cancer,the mtDNA common deletion was detected at low levels in some tumors and their normal adjacent tissues.The incidence was around about 5%-40%in breast, lung, esophageal and oral tumor tissues. The short deletion and insertion have been found in all five types of tumors. There was a high incidence of short deletion and insertion mutations occurring in lung and oral cancer. The mtDNA microsatellite instability was found in some cases of all types of tumors.The most common in lung cancer showed the highest incidence(66.7%),followed by oral caner(61.1%),esophageal(45%),and hepatic cancer(45%) and breast cancer(24.7%). CONCLUSION:mtDNA length instability indeed was a common phenomenon in different tumors.Some of them result in replication malfuction, gene malfuction, OXPHOS deficiency and transcription stop and it may play a potential important role in the tumorigenesis of these carcinomas.