The Uprising of Mitochondrial DNA Biomarker in Cancer

Abstract

Cancer is a heterogeneous group of diseases, the progression of which demands an accumulation of genetic mutations and epigenetic alterations of the human nuclear genome or possibly in the mitochondrial genome as well. Despite modern diagnostic and therapeutic approaches to battle cancer, there are still serious concerns about the increase in death from cancer globally. Recently, a growing number of researchers have extensively focused on the burgeoning area of biomarkers development research, especially in noninvasive early cancer detection. Intergenomic cross talk has triggered researchers to expand their studies from nuclear genome-based cancer researches, shifting into the mitochondria-mediated associations with carcinogenesis. Thus, it leads to the discoveries of established and potential mitochondrial biomarkers with high specificity and sensitivity. The research field of mitochondrial DNA (mtDNA) biomarkers has the great potential to confer vast benefits for cancer therapeutics and patients in the future. This review seeks to summarize the comprehensive insights of nuclear genome cancer biomarkers and their usage in clinical practices, the intergenomic cross talk researches that linked mitochondrial dysfunction to carcinogenesis, and the current progress of mitochondrial cancer biomarker studies and development.

Evaluation of Mitochondrial Function in Blood Samples Shows Distinct Patterns in Subjects with Thyroid Carcinoma from Those with Hyperplasia

“…To evaluate the metabolic status of the thyroid samples, we first assessed the number and subcellular distribution of mitochondria in fixed tissue sections by immunofluorescence (IF) using a specific antibody against the mitochondrial protein TOMM22 [ 46 ]. Consistent with data for total mitochondrial content in many tumors [ 46 , 47 ], total TOMM22 positive area per cell was highly variable and did not correlate with disease state ( Figure A2 ), and was therefore disregarded for subsequent analysis. Instead, we used TOMM22 IF signal to monitor two parameters indicative of mitochondrial dysfunction: the asymmetric distribution of mitochondria around the nucleus ( capping ) and the degree of mitochondrial fission [ 48 , 49 ].…”

Evaluation of Mitochondrial Function in Blood Samples Shows Distinct Patterns in Subjects with Thyroid Carcinoma from Those with Hyperplasia

“…Indeed, there are several approved clinical tests for the presence of cancer-associated genomic mutations or epigenetic modifications [16]. These developments, along with the identification of tumorspecific mtDNA mutations, have also spurred interest in the use of mtDNA as a potential biomarker [43]. However, specific applications in this regard have not yet been developed, possibly because most studies do not generally consider the metabolic changes in that occur in the tumor or in the organism as a whole.…”

“…To evaluate the metabolic status of the thyroid samples, we first assessed the number and subcellular distribution of mitochondria in fixed tissue sections by immunofluorescence (IF) using a specific antibody against the mitochondrial protein TOMM22 [42]. Consistent with data for total mitochondrial content in many tumors [43], total TOMM22 positive area per cell was highly variable and did not correlate with disease state (Fig. A2), and was therefore disregarded for subsequent analysis.…”

“…Mitochondrial oxidative stress can result in oxidative damage to mtDNA, deficient mtDNA replication and gradual loss of mtDNA [51]. Indeed, reduced levels of mtDNA have been found associated with some cancer types [43]. We analyzed mtDNA levels in tissue samples by qPCR and found that mtDNA levels were significantly lower in carcinomas than in hyperplasias (Fig.…”

Research highlights on contributions of mitochondrial DNA microsatellite instability in solid cancers – an overview

“…Moreover, mtDNA mutations have also been identified in a wide variety of cancers [ 24 , 25 ], since the first descriptions by Vogelstein’s team in 1998 [ 26 ], who revealed 70% of somatic mtDNA mutations in 7 of 10 human colorectal cancer cell lines. Mitochondrial DNA genome alterations in cancers commonly discovered either in the types of somatic mutations or germline polymorphisms include point mutations, deletions, insertions, mono- or dinucleotide repeats, and mtDNA copy number variations [ 24 ].…”