Qiao Lihua, Ru Guoqing, Mao Zhuochao, Wang Chenghui, Nie Zhipeng, Li Qiang, Huang-Yang Yiyi, Zhu Ling, Liang Xiaoyang, Yu Jialing, Jiang Pingping
Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Oncotarget. 2017 Sep 16;8(48):84373-84383. doi: 10.18632/oncotarget.21033. eCollection 2017 Oct 13.
We investigated the role of mitochondrial genetic alterations in hepatocellular carcinoma by directly comparing the mitochondrial genomes of 86 matched pairs of HCC and non-tumor liver samples. Substitutions in 637 mtDNA sites were detected, comprising 89.80% transitions and 6.60% transversions. Forty-six somatic variants, including 15 novel mutations, were identified in 40.70% of tumor tissues. Of those, 21 were located in the non-coding region and 25 in the protein-coding region. Twenty-two somatic nonsynonymous changes were identified as putative pathogenic variants, including 4 truncating mutations produced by three frameshifts ( 8628 insC; 13475 T-del, and 14984 insA) and 1 nonsense mutation in 9253 G>A. Among the somatic variants, only m.13676 A>G (), found in only 1 tumor, was heteroplasmic. Both inherited and somatic variants were predominately located in the D-loop region and the gene. Tumor/non-tumor paired analysis showed that 69% of HCC samples contained significantly reduced mtDNA, compared with 49.0% of non-tumor counterparts. In 81.40% of HCC samples, mitochondrial transcription factor A (TFAM) was enriched in tumor cells but not in adjacent non-tumor cells. Neither mtDNA depletion nor TFAM overexpression correlated with the degree of cell differentiation, though TFAM expression correlated with tumor size.
我们通过直接比较86对匹配的肝癌（HCC）和非肿瘤肝脏样本的线粒体基因组，研究了线粒体基因改变在肝细胞癌中的作用。检测到637个线粒体DNA（mtDNA）位点的替换，其中转换占89.80%，颠换占6.60%。在40.70%的肿瘤组织中鉴定出46个体细胞变异，包括15个新突变。其中，21个位于非编码区，25个位于蛋白质编码区。22个体细胞非同义变化被鉴定为推定的致病变异，包括由三个移码产生的4个截短突变（8628 insC；13475 T-del和14984 insA）以及9253 G>A中的1个无义突变。在体细胞变异中，仅在1个肿瘤中发现的m.13676 A>G（）是异质性的。遗传变异和体细胞变异主要位于D环区域和基因中。肿瘤/非肿瘤配对分析显示，与49.0%的非肿瘤样本相比，69%的肝癌样本中mtDNA显著减少。在81.40%的肝癌样本中，线粒体转录因子A（TFAM）在肿瘤细胞中富集，但在相邻的非肿瘤细胞中未富集。尽管TFAM表达与肿瘤大小相关，但mtDNA耗竭和TFAM过表达均与细胞分化程度无关。
