Mitochondrial DNA Variations in Tumors: Drivers or Passengers?

Abstract

Mitochondrial DNA alterations, including point mutations, deletions, inversions and copy number variations, have been widely reported in many age-related degenerative diseases and tumors. However, numerous studies investigating their pathogenic role in cancer have provided inconsistent evidence. Furthermore, biological impacts of mitochondrial DNA variants vary tremendously, depending on the proportion of mutant DNA molecules carried by the neoplastic cells (the so-called heteroplasmy). The recent discovery of inter-genomic crosstalk between nucleus and mitochondria has reinforced the role of mitochondrial DNA variants in perturbing this essential signaling pathway and thus indirectly targeting nuclear genes involved in tumorigenic and invasive phenotype. Therefore, mitochondrial dysfunction is currently considered a crucial hallmark of carcinogenesis as well as a promising target for anticancer therapy. This chapter describes the role of different types of mitochondrial DNA alterations by mainly considering the paradigmatic model of colorectal carcinogenesis and, in particular, it revisits the issue of whether mitochondrial mutations are causative cancer drivers or simply genuine passenger events. The advent of high-throughput next-generation sequencing techniques, as well as the development of genetic and pharmaceutical interventions for the treatment of mitochondrial dysfunction in cancer, are also discussed.

Analysis of mitochondrial dna control region d-loop in gliomas: result of 52 patients

“…Mean total variation numbers were relatively high in IDH1 R132 wild type and IDH/TERT double negative samples and also WHO grade IV GBM patients. These results suggest that the mitochondrial variation number is high in more aggressive gliomas, which is in line with the literature (8,10,11).…”

“…High frequency of variations was reported in this region, most (about 95%) of them being transitions that are associated with oxidative DNA damage (11). These variations do not lead to growth disadvantage for the cell and have been associated with risk, survival, prognosis, and/or response to therapies in different cancer types (8).…”

“…There are arguments suggesting the association of mitochondrial variants with cancer risk, survival rates, prognosis and response to certain therapies. These variants have been proposed as valuable prognostic markers (8). Therefore, the present study aimed to identify variations in the mtDNA control region D-loop in glioma which is a well-known hotspot region for somatic mutations in many cancer types.…”

Novel Strategies for Disrupting Cancer-Cell Functions with Mitochondria-Targeted Antitumor Drug–Loaded Nanoformulations

“…Therefore, mitochondrial dysregulation is currently regarded as an important hallmark of carcinogenesis and a promising target for antitumor therapy. 68 Moreover, the advancement of mtDNA editing tools is expected to improve strategies to characterize, track, and repair oncogenic mitochondria, which will further boost the understanding of mitochondrial epigenetics in cancer and therapeutic strategies.…”

Potential Association of Mitochondrial Haplogroups and A8860G Mutation with Breast Cancer Risk

“…To date several studies in different populations have been performed, figuring out significant relation between specific haplogroups and incidence of different cancers, including breast cancer [9, 10, 11, and 12] as well as identification of specific mutational variants in association with cancer cases in general as T16189C, G10398A and the deletion of mtDNA 4977 [13]. Mitochondrial DNA (mtDNA) is a circular molecule of 16569 bp, coding for two 2 ribosomal RNAs (12S and 16S), 22 transfer RNAs and 13 essential protein subunits of the oxidative phosphorylation system (OXPHOS) [14]. It is well known that (mtDNA) has a mutation rate several times higher than nuclear DNA [15], due to its limited repair mechanisms, lack of protective histones and its close proximity to the electron transport chain, which continuously generates free radicals [16]; in addition, mtDNA is organized in an economic pattern with its genes lacking introns [17].…”