Mitochondrial Genome Instability and mtDNA Depletion in Human Cancers

Abstract

An increase in the rate of glycolysis is one of the metabolic alterations in most cancer cells. However, the role of alterations in mitochondrial function and mitochondrial DNA (mtDNA) in carcinogenesis still remains unclear. In this study, we analyzed the nucleotide sequence of the D-loop and the copy number of mtDNA in 54 hepatocellular carcinomas (HCCs), 31 gastric, 31 lung, and 25 colorectal cancers as well as their corresponding non-tumorous tissues. The results revealed that 42.6% (23/54) of the HCCs, 51.6% (16/31) of the gastric cancers, 22.6% (7/31) of the lung cancers, and 40.0% (10/25) of the colorectal cancers harbored mutation(s) in the D-loop of mtDNA. The mtDNA mutations in 43.5% (10/23) of the HCCs, 62.5% (10/16) of the gastric cancers, 57.1% (4/7) of the lung cancers, and 90.0% (9/10) of the colorectal cancers were changes in the mononucleotide or dinucleotide repeats, deletions, or multiple insertions. Moreover, we found that there is a significant decrease in mtDNA copy number in 57.4% (31/54) of the HCCs, 54.8% (17/31) of the gastric cancers, 22.6% (7/31) of the lung cancers, and 28.0% (7/25) of the colorectal cancers compared with the corresponding non-tumorous tissues. It is noteworthy that the incidence of somatic mutations in the D-loop of mtDNA in the cancers of later stages was higher than that of the early-stage cancers. Taken together, our findings suggest that instability in the D-loop region of mtDNA, together with the decrease in mtDNA copy number, is involved in the carcinogenesis of human cancers.

Mitochondrial D-Loop Polymorphism and Microsatellite Instability in Prostate Cancer and Benign Hyperplasia Patients

“…D-Loop region is highly polymorphic and has two hypervariable segments: HVS1 (16093-16362) and HVS2 (150-372). Point mutations and mitochondrial microsatellite instability (mtMSI) occur frequently in these segments; moreover, the incidence of somatic mutations in this region in some cancers increases with the cancer stage (Lee et al, 2005). In contrast in another study there was no association between mitochondrial haplogroups and control region polymorphisms with prostate cancer (Mueller et al, 2009).…”

“…All prostate cancer patients carried D-loop variations in Gomez-Zaera et al's study (GomezZaera et al, 2006). In addition, various frequencies of the mtDNA alterations were identified in several types of malignancies including: glioma 35% (Kirches et al, 2001;Chatterjee et al, 2006), colorectal cancer 38%, (Lievre et al, 2005) hepatocellular carcinoma 39%, (Lee et al, 2005) osteosarcoma, 70% (Guo, 2006) and AML 79%, (Sharawat et al, 2010).…”

“…D-loop mutations and altrations are frequently found in various human cancers; therefore, it is known as a "hot spot" for point mutations in cancers. These mutations are considered to be the result of high concentrations of ROS and incompetent mtDNA repair system (Lee et al, 2005). Mitochondrial DNA polymorphism can act as risk modifier in late onset diseases such as cancers (Gomez-Zaera et al, 2006).…”

Association between Mitochondrial D-loop Polymorphism and Copy Number

“…종양에서의 mtCN는 두경부암, 난소암 및 식도암에서는 증가하였고 [18][19][20]. 간세포암, 위암, 유 방암 및 신세포 암에서는 감소하였다 [21][22][23][24][25] …”

Mitochondrial DNA repair in aging and disease

“…According to Carew and Huang, the main features of mtDNA mutations common to all tumor types are: (i) the majority of the mutations are base substitutions; (ii) mutations occur in all protein-coding mitochondrial genes; (iii) the D-loop region is the most frequent site of somatic mutations across most tumor types; and (iv) the mutations are homoplasmic in nature (119). Deletions of mtDNA, as well as insertion mutations, also are reported in many kinds of cancer (120). The homoplasmic nature of mutated mtDNA raises the possibility that some mutations are involved in tumorigenesis itself by affecting energy metabolism and/or ROS production.…”