Mitochondrial DNA and Cancer Epidemiology Workshop

September 7-8, 2006, Bethesda, Maryland

Additional Information

Mitochondrial DNA mutations are associated with numerous chronic diseases, including cancer. EGRP-hosted a meeting on September 7-8, 2006, in Bethesda, MD, to review the state-of-the science in the mitochondrial DNA field and its use in cancer epidemiology, and to develop a concept for a research initiative on mitochondrial DNA and cancer epidemiology. The meeting was sponsored by NCI's Analytic Epidemiology Research Branch (AERB), Epidemiology and Genetics Research Program (EGRP), Division of Cancer Control and Population Sciences (DCCPS).

The workshop participants included international leaders in the fields of mitochondrial biology, cancer epidemiology, oncology, and biotechnology. Keshav Singh, Ph.D., Roswell Park Cancer Institute, Buffalo, NY, and Robert Naviaux, M.D., Ph.D., University of California, San Diego, chaired the meeting.

Brief talks covered the following topics: examples of different tumor types for which mitochondrial DNA has been used for diagnosis, interaction of nuclear and mitochondrial genomes, mitochondrial haplogroups and cancer, other mitochondrial diseases and cancer, and high-throughput technologies to detect mitochondrial DNA mutations and polymorphisms.

The general consensus of the participants was that there is a need to utilize information from the mitochondrial genome in cancer epidemiology to understand the etiology of the disease and to utilize mitochondrial somatic mutations and mitochondrial haplotypes in screening populations of different ethnicities.

Mitochondria have been implicated in the process of carcinogenesis because of their vital role in energy production, nuclear-cytoplasmic signal integration, and control of metabolic pathways. Interestingly, at some point during neoplastic transformation, there is an increase in reactive oxygen species, which damages the mitochondrial genome. This accelerates the somatic mutation rate of mitochondrial DNA. It has been proposed that these mutations may serve as an early indication of potential cancer development and may represent a means for tracking tumor progression.

Mitochondrial dysfunction is a hallmark of cancer cells. Mutations have been detected in mitochondria of different tumor types, including breast, colon, esophageal, endometrial, head and neck, hepatocellular, kidney, leukemia, lung, melanoma, oral, prostate, and thyroid cancer. However, it is not clear whether mitochondrial genomic status in human cells affects nuclear genome stability and whether proteins involved in intergenomic cross talk are involved in tumorigenesis. Somatic mitochondrial mutations are common in human cancers, and can be used as a tool for early detection of cancer. The majority of these somatic mutations are homoplasmic in nature, indicating that the mutant mtDNA become dominant in tumor cells.

One approach to understand the utility of mitochondrial DNA in cancer epidemiology is to look for the somatic mutations in mitochondria, and the other approach is to look for disease-associated haplotypes. The inheritance pattern of mitochondria in patients with cancer has been studied by haplotype analysis. Polymerase chain reaction of key polymorphic sites in the mitochondrial genome was performed in samples from cancer patients and normal individuals to determine if there is an association between mitochondrial genotype and cancer. Such analysis has been accomplished in prostate and renal cancer.

A variety of clinical samples have been utilized for mitochondrial DNA mutation detection. For example, nipple aspirate and paraffin-embedded specimens for breast cancer, urine for bladder cancer, buccal cells for head and neck cancer, cerebrospinal fluid for meduloblastoma, and sputum for lung cancer have been used. High-throughput mutation analysis of mtDNA is performed on "MitoChips" with the whole mitochondrial genome (16.5 kb).

For epidemiologic studies in which thousands of samples are collected and analyzed, it is very important to select which clinical samples should be collected. The procedure should be noninvasive and not expensive. It would be ideal to have three specific tissue types for any mtDNA study: blood, tumor, and normal tissue adjacent to the tumor. The reason for collecting three types of biospecimens is the existence of mitochondrial genome in homoplasmic and heteroplasmic forms. Samples collected from tumors and adjacent sites will indicate whether mitochondrial homoplasmy is maintained or not. Because NCI maintains a number of cohorts, nested case-control studies should be designed for evaluating mitochondrial DNA markers for risk assessment. The specific topics of interest to EGRP are:

  • Will inclusion of mitochondrial markers help to identify new risk factors (modifiable factors and host factors) in different races and ethnic groups?
  • Will mitochondrial markers in cohort and case-control studies improve sensitivity and specificity of markers and help in identifying 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?

There is an urgent need to utilize mitochondrial DNA somatic mutations and deletions as markers for epidemiological purposes that help us identify high-risk populations in different races and ethnic groups, said Mukesh Verma, Ph.D., Acting Chief of AERB.

For more information about this meeting, see the meeting agenda. In addition, an article summarizing this meeting was published in the January 15, 2007 issue of the journal Cancer Research:

Verma M, Naviaux RK, Tanaka M, Kumar D, Franceschi C, Singh KK. Meeting report: mitochondrial DNA and cancer epidemiology. Cancer Res. 2007 Jan 15;67(2):437-9.

Workshop Organized by Mukesh Verma, Ph.D.