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Introduction to MtDNA: A Burgeoning Biomarker in Cancer

July 15, 2022
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The rapid growth of liquid biopsy research and usage is reflected in the proliferation of liquid biopsy companies, VC investment, and a steady increase in market size*. With this surge, biomarkers like mtDNA, in addition to more “traditional” analytes (e.g., ctDNA, cfDNA, proteins), are being pursued. Mitochondria have their own genetic code, mtDNA, which is separate from nuclear DNA. mtDNA contains 37 genes that encode proteins essential for oxidative phosphorylation, the primary source for ATP. The circular, double stranded molecule has notable differences compared to its nuclear counterpart [1].

mtDNA Mutations in Diseases

Abnormalities in the mitochondrial genome can cause mitochondrial dysfunction, which contributes to an array of diseases. The genome’s naive endogenous repair mechanisms result in a mutational rate in the mitochondrial genome that is 5- to 10-fold higher than in its nuclear counterpart. The mutations are especially damaging given the high copy number and absence of introns. Single nucleotide polymorphisms (SNPs) in mtDNA are usually inherited together, forming mitochondrial haplogroups. Haplogroups consist of individuals with similar aggregations of mitochondrial SNPs, which are maternally inherited without any recombination [1].

In the late 90s, the association between a singular mitochondrial haplogroup and Leber Hereditary Optic Neuropathy was discovered. Since then, studies have ascertained the association between mtDNA population variants and other neurodegenerative diseases including Alzheimer’s, Parkinson’s, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis [2]. The unique vulnerabilities of the mitochondrial genome contribute to the prevalence of mtDNA disease.

mtDNA as a Biomarker

Since the first report of somatic mtDNA mutation associated with cancer two decades ago, the International Cancer Genome Consortium and the Cancer Genome Atlas have validated that about 60% of solid tumors have at least one mtDNA mutation. Alterations in mtDNA transcription and expression levels, as well as copy number, may contribute to and/or reflect cancer occurrence and metastasis [3]. The short length, relatively simple structure, high abundance, and ability to serve as liquid biopsy affirm the value of mtDNA as a non-invasive biomarker. A recent study of triple-negative breast cancer used mtDNA differences in tumor cells to identify patients at a greater risk of metastasis, thereby elucidating more appropriate therapy options [4]. Another study presented promising results for MRD detection through mtDNA mutations in leukemia patients [5]. The results of several studies have shown a 14-fold higher mean mtDNA level in bladder, kidney, and prostate cancer patients [6]. By shedding light on cancer presence and clinicopathological characteristics such as tumor stage, mtDNA provides the option for a more specific liquid biopsy.

Another mtDNA associated biomarker is Cell-free mtDNA (cf-mtDNA). The release of cf-mtDNA into the cytosol or blood is caused by the disruption of the mitochondrial life cycle along with compromised mitophagy (the turnover of damaged or excess mitochondria). cf-mtDNA has been recommended as a biomarker for diabetes risk and metabolic syndrome. The latter is highly correlated with an increased risk of common cancers [8].

Commercial Momentum

Currently on the market is the Mitomic™ Prostate Test from MDNA Life Sciences, which looks for a 3.4kb mtDNA deletion to determine risk of significant prostate cancer. MDNA also has an endometriosis screening test and is currently developing additional blood-based mtDNA tests for ovarian and lung cancer screening. Dr Andrew Harbottle, MDNA Life Sciences’ Chief Science Officer says: “We exploit the unique characteristics of mutations in mitochondrial DNA, which can act as biomarkers, providing us with a unique and detailed diary of damage to the DNA. This enables us to accurately detect many difficult to diagnose diseases and conditions, such as prostate cancer.” Further, the positive results from clinical trials involving MRD and therapy selection anticipate an expanding role for mtDNA in the liquid biopsy field.


The mitochondrial genome is susceptible to mutations, many of which are associated with neurodegenerative diseases and cancer. Its unique characteristics make mtDNA an accessible and non-invasive biomarker candidate for solid tumor diagnostics and prognostics. Several studies have demonstrated sensitivity and specificity of mtDNA tests in differentiating cancer patients from healthy controls [6]. Ongoing research anticipates establishing a consensus for interpretation of test results. There has been a flurry of activity in recent years in the mitochondrial therapeutics space, and more commercial liquid biopsies that detect mtDNA are expected to enter the market. From clinical studies and research results, there is growing interest in the analysis of mtDNA in personalized medicine and hope for the reduction of excessive and invasive cancer testing methods. If you are also excited about mtDNA and developments in liquid biopsy, reach out to us!










* Ten year forecast predicts a 13.5% compound annual growth rate from USD 7.03 billion in 2020

Jackie Wang
Summer Analyst
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