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

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.