Mitochondrial D-loop mutations and deletion profiles of cancerous and noncancerous liver tissue in hepatitis B virus-infected liver

Abstract

The largest single underlying cause of hepatocellular carcinoma (HCC) worldwide is hepatitis B virus (HBV) infection. Hepatitis B virus increases cellular oxidative stress and the development of HCC occurs after a long latency period. The study was carried out to determine whether mitochondrial DNA abnormalities were associated with HCC in individuals with HBV. The frequency of mutation and deletion of specific areas of the mitochondrial genome in tumour and matched normal tissue of patients with HBV infection was investigated in the current study. The percentage of control subjects harbouring D-loop mutations was 11%, which was significantly lower than that observed in both the noncancerous (49%, P ¼ 0.033) and tumour tissue (59%, P ¼ 0.014) of patients with HCC. In contrast, the number of cases in which the common 4977 bp deletion of the mitochondrial genome was detected was significantly greater in control liver and noncancerous liver tissue of subjects with HCC (100 and 95%, respectively) than in cancerous liver tissue (28%, Po0.001). These observations suggest that the inflammatory process contributes to the rate of mitochondrial mutations. However, the lower frequency of the large deletion in cancerous tissue suggests that there is selection against either mitochondria, which harbour large deletions, or against cells that contain these mitochondria during hepatocarcinogenesis.

Circulating Mitochondrial DNA Content Associated with the Risk of Liver Cirrhosis: A Nested Case–Control Study

“…mtDNA content is required to maintain normal mitochondrial respiratory function. Decreased mtDNA content in cirrhosis may be ascribed to (1) interference with the replication and maintenance of mtDNA through point mutations located in the D-loop region, and (2) impairment of mitochondrial biogenesis by reduced expression of involved proteins, such as mitochondrial single-stranded DNA-binding protein and mitochondrial transcription factor A [21,22,31,34,35]. Reduced mtDNA content could lead to impaired oxidative phosphorylation capacity, thus enhancing ROS production and promoting DNA damages which may lead to malignant transformation [36].…”

Associations between sequence variations in the mitochondrial DNA D-loop region and outcome of hepatocellular carcinoma

“…Lee et al (22) examined mutations in the D-loop region of mtDNA in 61 HCC specimens, and the results demonstrated that 39.3% carried somatic mutation(s) in the mtDNA D-loop. Furthermore, Wheelhouse et al (23) reported that the percentage of tumour tissue from patients with HCC harbouring D-loop mutations was 59%. However, in other studies, mtDNA mutations were not ubiquitous, which is comparable to the present study (24).…”

Mitochondrial DNA mutations in human cancer

“…The frequency of subjects harboring a D-loop mutation, was significantly greater in the liver tissue of subjects with HCC compared with normal control cases (59 vs 11%) while the incidence of deletion in mtDNA was significantly lower in patients with HCC (Wheelhouse et al, 2005). In an earlier study involving direct sequencing of mtDNA in 54 hepatocellular carcinomas (HCCs), mtDNA alterations were found in the D-loop region both in the HCC and the non-cancerous liver tissue.…”