Mitochondrial A12308G alteration in tRNA Leu(CUN) in colorectal cancer samples

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].