Various human diseases have been associated with mtDNA mutations, indicating that dysfunction of the components of oxidative phosphorylation encoded by the mitochondrial genome can be deleterious [
21]. Abnormalities in mtDNA have proven to be associated with leber’s hereditary optic neuropathy (LHON) [
22], Primary open-angle glaucoma (POAG) [
23,
24], pseudoexfoliation glaucoma (PEG), primary angle closure glaucoma (PACG), other spontaneous optic neuropathies [
25‐
27] and male infertility [
28]. Moreover, 25-80 % of somatic mutations in mitochondrial DNA are found in various neoplasms [
29]. Also, in 2012 the role of the mitochondrial tRNA genes was analyzed in patients with asthma compared with a set of healthy controls. They suggested that the mitochondrial tRNA genes play a key role in asthma development [
30]. The use of mtDNA mutation patterns as a biomarker is rapidly expanding in rare metabolic diseases, aging, cancer, tracing of human migration patterns, population characterization and human identification in forensic science [
31]. It seems that the mitochondrial genome is more useful in detecting tumor cells in body fluids and cytological specimens than mutations in nuclear DNA had been confirmed.
In the present study, to the best of our knowledge, this is the first reported association between colorectal cancer and mtDNA A12308G alteration in tRNALeu(CUN). The A12308G change was introduced as a common polymorphism by Houshmand at the first time [
14]. Several studies described the association of mt-tRNA mutations with human cancers. This mutation came to the attention of the breast cancer research communities as a plausible candidate marker for increased breast cancer susceptibility [
29,
32]. In USA, the A12308G polymorphism was introduced as an important factor in kidney and prostate cancer risk [
16]. In India, the A12308G mutation was seen as a significant change in the risk of oral cancer [
33]. This alteration was, also, reported as a multiplier risk factor in advanced breast cancer tumors in European – American patients [
34]. Increased prevalence of the A12308G mutation in mitochondrial tRNA
Leu(CUN)gene associated with Friedreich's ataxia in Iran, was reported [
35]. In previous studies, A12308G alteration has occurred in association with another disease causing alteration in MELAS, myopathy and primary congenital glaucoma (PCG) where three such changes (G10398A, A12308G and G13708A) were present in the later [
36,
37]. Moreover, the A12308G polymorphism in tRNA
Leu(CUN) increases the risk of developing stroke in patients with the A3243G mutation [
38]. So, this polymorphism may act as a secondary mutation in this disease pathogenicity. The A12308G variation is also associated with increased ROS production [
39]. Nine main European haplotypes (H, I, J, K, T, U, V, W and X) were analyzed in a series of patients with prostate and renal cancers studied by Booker et al. Using the A12308G substitution in tRNA
Leu as a marker of the mtDNA haplogroup U, it was found that patients carrying this haplogroup had an increased risk of renal and prostate cancer [
16]. Some studies showed an increased frequency of the A12308G substitution in mitochondrial patients carrying mtDNA single macrodeletion. In this group of patients, A12308G substitution is associated with a higher relative risk of developing pigmentary retinal degeneration, short stature, dysphasia–dysarthria and cardiac conduction defects [
40]. Moreover, the A12308G was found in 8 Alzheimer’s disease patients [
41]. In the case of endometrial adenocarcinoma the presence of mitochondrial A12308G alteration in tRNA
Leu(CUN) was reported [
42,
43]. Study in Italy stated that Mitochondrial DNA mutations have been causally linked with cardiomyopathies, both dilated (DCM) and hypertrophic. They identified the T12297C mutation in the mtDNA-tRNA
Leu(CUN) of a patient diagnosed with DCM. In the variable loop of the same tRNA, their patient also carried the A12308G transition [
44].