Tumors pose an increasing threat to human health. Mitochondria play significant roles in cellular energy metabolism and free radical generation and have therefore become a focus of cancer research. Warburg studied the changes of mitochondrial structure and function in tumor cells as early as 1956 (8
). When the role of mitochondria in cellular apoptosis was identified (9
), researchers studied the correlation between tumors and the mitochondria and thus began to show interest in the changes of the mitochondrial genome in tumor tissues.
Certain studies have demonstrated that the dysfunction of mitochondria may cause the origin and progression of tumors. For example, certain inherited mutations of nuclear genes that encode proteins which take part in the mitochondrial tricarboxylic acid cycle cause mitochondrial deficiencies and lead to tumor development (10
). A fraction of mtDNA mutations identified in human tumor cells are considered to have significant effects on mitochondrial function (11
). In summary, the mtDNA mutations causing mitochondrial dysfunction may be the cause of tumorigenesis.
To date, studies on the mutations in the mitochondrial genome have been performed in various tumors. Somatic mtDNA mutations have been reported in various tumor types, including breast, colorectal, bladder, gastric, esophageal, lung and oral cancer, head and neck neoplasm and leukemia. These mtDNA mutations include point mutations, deletions and insertions (12
). The roles that these mtDNA mutations play in tumorigenesis and tumor development have not been determined.
Methods used to detect mtDNA mutations
Somatic mutations are defined as the variants that exist only in the cancerous tissue and not in the corresponding normal tissue. Conversely, the variants that exist in cancerous tissue and in normal tissue are defined as germline mutations. In general, the single-strand conformation polymorphism analysis (SSCP), denaturing high-performance liquid chromatography (DHPLC), temporal temperature gradient electrophoresis (TTGE), as well as direct sequencing (22
), which all are based on the PCR method, are used to detect the somatic mtDNA mutations and germline mtDNA mutations. Heteroplasmy occurs when the wild-type and mutant mtDNA coexist in the tissues or cells; otherwise it is named homoplasmy (15
General features of the mtDNA mutations
The mtDNA mutations identified in various tumor cells or tissues present 3 features that are independent of the type of cancer.
First, the majority of the mtDNA mutations observed are the T to C and G to A base transitions. This is similar to the mutation pattern of oxidative decay on DNA caused by ROS in normal tissues. Hence, it may be deduced that the main cause of mtDNA mutations in tumors is the elevated high level of ROS (23
Second, the D-loop region is the mutational hotspot. The D-loop region of human mitochondrial genome is 1,122 bp long. It is the main control area for the duplication and transcription of mtDNA and includes the primary transcript promoter and leading strand for the origin of replication of mtDNA (1
). Previous research has revealed the D-loop region as the mutational hotspot in various types of cancer, including breast and bladder cancer and head and neck neoplasms, and also in the normal human population. Therefore, the high mutational frequency in the D-loop region may not lead to the specific changes in tumors. The D-loop is the site that the mtDNA is nearest to the mitochondrial inner membrane and thus is most susceptible to the damage of ROS (24
Third, the majority of the mtDNA mutations detected are homoplasmic. Numerous mtDNA mutations have been reported in various tumor tissues; some were somatic and others were germline mutations (12
). Of note, the majority of these mutations were homoplasmic. This observation has been interpreted to reflect a replicative advantage for mutated mtDNA copies, or a growth advantage for a cell containing certain mtDNA mutations; thus these mutations may become homoplasmic rapidly during cell fissions and become fixed (11
). However, Coller et al
considered that the observed homoplasmy arose entirely by chance in tumor progenitor cells, without any physiological advantage or tumorigenic requirement (28
). Through extensive computer modeling, the authors demonstrated that there are sufficient opportunities for a tumor progenitor cell to achieve homoplasmy through unbiased mtDNA replication and sorting during cell division. They revealed that the predicted frequency of homoplasmy in tumor progenitor cells in the absence of selection is similar to the reported frequency of homoplasmic mutations in tumors (27
). Additionally, Jones et al
reported that the somatic mtDNA mutations in a tumor progenitor cell were capable of undergoing ‘genetic drift’ to obtain a homoplasmic status through 1,000 or more mitochondrial segregations (28
). Chinnery et al
also suggested that random genetic drift was sufficiently powerful to explain the homoplasmy and fixation of rare mtDNA mutations in tumor tissues (29