Mitochondrial DNA depletion, mitochondrial mutations and high TFAM expression in hepatocellular carcinoma

// Lihua Qiao 1, 2, * , Guoqing Ru 3, * , Zhuochao Mao 2, 4, * , Chenghui Wang 1, 2 , Zhipeng Nie 1, 2 , Qiang Li 1, 2 , Yiyi Huang-yang 2 , Ling Zhu 1, 2 , Xiaoyang Liang 1, 2 , Jialing Yu 2, 5 and Pingping Jiang 1, 2 1 Division of Medical Genetics and Genomics, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China 2 Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China 3 Department of Pathology, The Zhejiang Provincial People’s Hospital, Hangzhou, China 4 Department of Surgical Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China 5 School of Public Health, Zhejiang University, Hangzhou, China * These authors have contributed equally to this work Correspondence to: Pingping Jiang, email: ppjiang@zju.edu.cn Keywords: mitochondrion, hepatocellular carcinoma, somatic mutation, DNA copy number, TFAM Received: May 19, 2017 Accepted: August 17, 2017 Published: September 16, 2017 ABSTRACT 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 ( MT-ATP6 8628 insC; MT-ND5 13475 T-del, and MT-CYB 14984 insA) and 1 nonsense mutation in MT-CO3 9253 G>A. Among the somatic variants, only m.13676 A>G ( MT-ND5 ), found in only 1 tumor, was heteroplasmic. Both inherited and somatic variants were predominately located in the D-loop region and the MT-ND5 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.