May 01

A Tale of Two Genomes: Mitochondrial Genomics and Cancer Risk

Mitochondria play important roles in cellular energy metabolism, free radical generation, and apoptosis, and as a result, mitochondrial variations that affect these functions may contribute to the development and progression of cancer. In most cases, reactive oxygen species and DNA adducts induce mitochondrial mutations. Other agents that may result in mutations include radiation, infectious agents, and the ingredients of tobacco.

Picture of Mitochondrial DNA from the National Human Genome Research Institute

Mitochondrial DNA is the small circular chromosome found inside mitochondria. Mitochondria are organelles found in cells that are the sites of energy production. Mitochondria, and thus mitochondrial DNA, are passed from mother to offspring. Retrieved from National Institutes of Health. “Talking Glossary of Genetic Terms.” National Human Genome Research Institute. 26 April 2012, from http://www.genome.gov/glossary/?id=129

Mitochondria contain their own genome, and this genome codes for 37 genes. Additionally, mitochondrial DNA (mtDNA) contains a non-coding control region, which accounts for about 6 percent of the mitochondrial genome and has a high rate of variation. The number of mtDNA molecules per mitochondrion varies, as does the number of mtDNA copies in a cell (based on cell type). mtDNA mutates at a rate that is 10 to 20 times higher than that observed in nuclear DNA.

Somatic mtDNA mutations have been reported in different tumor types, and some reports indicate inherited mitochondrial DNA polymorphisms in cancer. Most somatic mutations are homoplasmic (i.e., all mutations in all copies of the mitochondria are the same), indicating that the mutant mtDNA becomes dominant in the tumor cells. The number of copies of mtDNA per cell varies in the normal and disease state. Because mtDNA lacks introns, research suggests that most mutations will occur in coding sequences, and subsequent accumulation of mutations may lead to tumor formation.

Some examples of cancer epidemiology studies with germline biospecimens that investigated mtDNA alterations and cancer risk include:

Fostering Research

In 2006, NCI’s Epidemiology and Genomics Research Program (EGRP) convened a workshop on mitochondrial DNA and cancer epidemiology and identified the importance of using information from the mitochondrial genome in cancer epidemiology. In 2008, NCI published two Program Announcements (PA) — an R01 and an R21 — to support applications proposing to develop and validate new mitochondrial-related biomarkers for cancer early detection, diagnosis, prognosis, risk assessment, and response to preventive and ameliorative treatments. These PAs were reissued in 2010 and expire January 8, 2014, as PA-11-073 (R01) and PA-11-074 (R21). EGRP also welcomes investigator-initiated grant applications using other R01s to study changes in mitochondrial DNA in relation to cancer epidemiology.

Specific scientific questions of interest to EGRP include, but are not limited to, the following:

  • Will inclusion of mitochondrial markers help to identify new risk factors (modifiable factors, host factors) in different races and ethnic groups?
  • Will mitochondrial markers in cohort and case-control studies improve their sensitivity and specificity and help identify high-risk populations?
  • Are genetic and mitochondrial DNA alterations (somatic mutations, deletions) correlated during cancer development?
  • Can we utilize mitochondrial haplogroup information to identify high-risk populations?
  • How can we utilize mitochondrial proteomic information to understand gene-gene and gene-environment studies and cancer etiology?

Available Research Resources

EGRP has created a new Web page containing research resources relevant to mitochondrial DNA and cancer epidemiology, including a list of funded grants, relevant research databases and tools, and selected publications that discuss techniques for measuring mtDNA alterations.

Tools to characterize and measure mtDNA characteristics are now available (including MitoChip) that can be used in epidemiologic studies and are sufficiently high throughput for the large numbers of samples analyzed in epidemiologic studies.

Almost all biospecimens can be used for mitochondrial DNA mutation detection. However, for mtDNA studies, it is ideal to have three specific tissue types: blood, tumor, and normal tissue adjacent to the tumor. Three types of biospecimens are collected because of the existence of mitochondrial genome in homoplasmic and heteroplasmic forms (mixture of more than one type of mtDNA). Samples collected from tumors and adjacent sites will indicate whether mitochondrial homoplasmy is maintained or not and also determine whether alterations are somatic or germline. View a compilation of biospecimen resources for population scientists, and see earlier blog posting “Leveraging Existing Biospecimen Resources to Advance Cancer Epidemiology Research.”

If you are aware of other resources not listed on our site, please let us know.  We look forward to hearing from you.


Picture of Mukesh VermaMukesh Verma, Ph.D., is Chief of EGRP’s Methods and Technologies Branch (MTB). He oversees MTB’s research portfolio and initiatives that focus on methods to address epidemiologic data collection, study design and analysis, and to modify technological approaches developed in the context of other research endeavors for use as biomarkers and methods to understand cancer susceptibility. Prior to joining EGRP, Dr. Verma was in NCI’s Division of Cancer Prevention, where he worked in the areas of biomarkers, early detection, risk assessment, and prevention. Dr. Verma earned his Ph.D. in host-virus interaction from Banaras Hindu University, and he also completed a Master of Science at Pantnagar University, where he majored in biochemistry and minored in microbiology.


  1. john

    are these including blood cancer?

    1. kaeferc


      Thank you for your question submitted in response to Mukesh Verma’s blog post. Dr. Verma confirmed that mitochondrial DNA (mtDNA) mutations have been reported in leukemia, primarily in the D-loop region. If you would like to do some additional reading, some references that may be of interest include:

      • Meierhofer, D, Ebner, S, Mayr, JA, Jones, ND, Kofler, B, and Sperl, W. Platelet transfusion can mimic somatic mtDNA mutations. Leukemia. 2006 Feb 20 (2): 362-363.

      • Sharawat, SK, Bakhshi, R, Vishnubhatla, S, and Bakhshi, S. Mitochondrial D-loop variations in paediatric acute myeloid leukaemia: a potential prognostic marker. Br. J. Haematol. 2010 May; 149 (3), 391-8.

      • Kwok CS, Quah TC, Ariffin H, Tay SK, Yeoh AE. Mitochondrial D-loop polymorphisms and mitochondrial DNA content in childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2011 Aug;33(6):e239-44.

      The Cancer Epidemiology Matters Blog Team

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