Mitochondrial DNA somatic mutations (point mutations and large deletions) and mitochondrial DNA variants in human thyroid pathology -: A study with emphasis on Hurthle cell tumors
Mitochondrial DNA somatic mutations (point mutations and large deletions) and mitochondrial DNA variants in human thyroid pathology -: A study with emphasis on Hurthle cell tumors
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DOI：
10.1016/s0002-9440(10)61132-7
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发表时间：
2002-05-01
影响因子：
6
通讯作者：
Sobrinho-Simoes, M
中科院分区：
文献类型：
--
作者：
Máximo, V;Soares, P;Sobrinho-Simoes, M
为了进一步了解线粒体DNA （mtDNA）改变与甲状腺肿瘤发生的关系，我们研究了79例良性和恶性肿瘤（43例Hurthle细胞瘤和36例非Hurthle细胞瘤）及其正常实质组织的mtDNA。采用半定量聚合酶链反应评价mtDNA共缺失（CD）。通过直接测序70%的线粒体基因组（包括所有13个OXPHOS系统基因），在66例肿瘤（59例患者）及其邻近实质中寻找体细胞点突变和mtDNA序列变异体。我们在34个肿瘤中检测到57个体细胞突变，主要是过渡，在59例患者中检测到253个序列变异。与腺瘤相比，滤泡癌和乳头状癌携带复合物I基因非沉默点突变的发生率明显更高。我们还发现复合体I和复合体IV序列变异在恶性肿瘤附近的正常实质中明显更高的患病率。每个Hurthle细胞肿瘤都显示出相对较高的mtDNA CD百分比（高达16%），与病变的组织型无关。在D-loop突变的肿瘤中，mtDNA分子缺失的百分比明显高于mtDNA稳定的肿瘤。ATPase 6基因是一种被认为在酵母mtDNA维持和完整性中起作用的复杂V基因，其序列变异在Hurthle细胞肿瘤患者中比在非Hurthle细胞肿瘤患者中更为普遍。综上所述，复合体I和复合体IV基因的mtDNA变异和mtDNA体细胞突变似乎参与了甲状腺肿瘤的发生。ATPase 6基因的种系多态性与mtDNA CD的发生有关，mtDNA CD是Hurthle细胞肿瘤的标志。
In an attempt to progress in the understanding of the relationship of mitochondrial DNA (mtDNA) alterations and thyroid tumorigenesis, we studied the mtDNA in 79 benign and malignant tumors (43 Hurthle and 36 non-Hurthle cell neoplasms) and respective normal parenchyma. The mtDNA common deletion (CD) was evaluated by semiquantitative polymerase chain reaction. Somatic point mutations and sequence variants of mtDNA were searched for in 66 tumors (59 patients) and adjacent parenchyma by direct sequencing of 70% of the mitochondrial genome (including all of the 13 OXPHOS system genes). We detected 57 somatic mutations, mostly transitions, in 34 tumors and 253 sequence variants in 59 patients. Follicular and papillary carcinomas carried a significantly higher prevalence of nonsilent point mutations of complex I genes than adenomas. We also detected a significantly higher prevalence of complex I and complex IV sequence variants in the normal parenchyma adjacent to the malignant tumors. Every Hurthle cell tumor displayed a relatively high percentage (up to 16%) of mtDNA CD independently of the lesion's histotype. The percentage of deleted mtDNA molecules was significantly higher in tumors with D-loop mutations than in mtDNA stable tumors. Sequence variants of the ATPase 6 gene, one of the complex V genes thought to play a role in mtDNA maintenance and integrity in yeast, were significantly more prevalent in patients with Hurthle cell tumors than in patients with non-Hurthle cell neoplasms. We conclude that mtDNA variants and mtDNA somatic mutations of complex I and complex IV genes seem to be involved in thyroid tumorigenesis. Germline polymorphisms of the ATPase 6 gene are associated with the occurrence of mtDNA CD, the hallmark of Hurthle cell tumors.