Meeting Report: Mitochondrial DNA and Cancer Epidemiology

The Analytic Epidemiology Research Branch of the National Cancer Institute (NCI) hosted a meeting on “Mitochondrial DNA and Cancer Epidemiology” in Bethesda, Maryland, on September 7 to 8, 2006 to review progress in the area of mitochondrial DNA (mtDNA) and its use in cancer epidemiology and risk assessment. International leaders in the fields of mitochondrial biology, cancer epidemiology, oncology, and biotechnology participated in the meeting. Mitochondria have been implicated in carcinogenesis because of their vital role in energy production, nuclear-mitochondrial and mitochondria-to-nucleus signal integration, control of apoptosis, and various metabolic pathways. During neoplastic transformation, there is an increase in reactive oxygen species (ROS) that damages the mitochondrial genome accelerating the somatic mutation rate in mtDNA. These mutations may serve as an early indication of potential cancer development and may represent a means for tracking tumor progression and therapeutic response. Workshop participants discussed mtDNA haplotype-associated risk in human population and recommended that the somatic mutations in mtDNA should be analyzed in conjunction with nuclear DNA in future studies of cancer epidemiology.Mitochondria play important roles in cellular energy metabolism, free radical generation, and apoptosis. Mitochondrial structure is dynamic and varies according to cell type and environmental conditions. In oocytes, they are 300 to 600 nm spheres. In fibroblasts, they are thread-like filaments measuring 0.4 × 2 μm to 0.4 × 8 μm. In other cell types, mitochondria appear as a dynamic, interconnected network, with fission and fusion events occurring throughout the cell cycle. In all cell types, mitochondria display close connections with the cytoskeleton and supply energy to the cell through the process known as oxidative phosphorylation. Mitochondria contain their own DNA, a 16.6-kb circular molecule that encodes 13 proteins, 22 tRNAs, and 2 rRNAs. In addition, ∼1,500 other proteins, including all the proteins required for mitochondrial transcription, translation, protein folding, and assembly, are encoded by genes in the nucleus and imported from the cytoplasm. These nucleus-encoded, mitochondrial proteins are tailored by the transcriptional program of cells so that every mitochondrion performs both tissue-specific and housekeeping metabolic functions. Because mtDNA lacks introns, most mutations occur in coding sequences and subsequent accumulation of mutations can lead to the development of tumors.The goal of the meeting was to get recommendations from experts in mitochondria and cancer epidemiology fields to provide information on cancer epidemiology, which helps to identify high-risk populations and to develop cancer control strategies. The meeting was chaired by Dr. Keshav Singh (Roswell Park Cancer Institute, Buffalo, NY) and cochaired by Dr. Robert K. Naviaux (University of California, San Diego, CA). Thirteen talks addressed the scientific issues related to mtDNA and risk of cancer. These include various tumor types containing mutant mtDNA, use of mtDNA early detection of cancer, factors contributing to alterations in mitochondrial genome, interaction of mitochondrial and nuclear genomes, mitochondrial haplogroups and associated cancer risks, and high-throughput technologies to detect mtDNA mutations and polymorphisms.Mitochondrial dysfunction(definition) is a hallmark of cancer cells. Mitochondrial dysfunction can lead to resistance to apoptosis and to the well-known Warburg effect associated with aerobic glycolysis. Somatic mtDNA mutations have been detected in various tumors and have been suggested as markers for early detection. The majority of these somatic mutations are homoplasmic in nature, indicating that the mutant mtDNA becomes dominant in tumor cells. However, it is not clear whether the status of mtDNA affects nuclear genomic stability or whether the proteins involved in intergenomic cross-talk are involved in tumorigenesis. To understand the use of mtDNA in cancer epidemiology, one approach is to look for the somatic mutations in mitochondria; another approach is to look for disease-associated haplotypes and the single-nucleotide polymorphisms (SNP) associated with those haplotypes. The inheritance pattern of mitochondria in patients with cancer has been studied by haplotype analysis.The meeting began with an overall presentation, summary of the field of mitochondria and cancer, and discussion by Dr. Singh about the importance of mitochondria-to-nuclear retrograde response in tumorigenesis. Dr. Singh showed that loss of mitochondrial function leads to cell cycle arrest, cellular senescence(definition), and tumorigenic phenotype. In light of these and earlier studies, he hypothesized the existence of a mitochondria damage checkpoint (mitocheckpoint) in human cells. The mitocheckpoint permits cells to arrest in the cell cycle to repair/restore mitochondrial function to the normal level. On overwhelming, persistent, or severe damage to mitochondria, mitocheckpoint machinery may allow cells to undergo senescence. Consequently, cellular senescence may function as another checkpoint before cells initiate programmed cell death resulting in aging of tissues and organs. Alternatively, mutations occur in the mitochondrial and/or nuclear DNA, resulting in tumorigenesis. Mitochondrial dysfunction resulting from changes in mtDNA invokes mitochondria-to-nucleus retrograde response in human cells. Dr. Singh's group carried out a comparative proteomic analysis using a cell line in which the mitochondrial genome was completely depleted (ρ0, cells lacking all mtDNA-encoded protein subunits), a cybrid cell line in which mtDNA was restored, and the parental cell line. His studies showed that retrograde proteins function as tumor suppressors or oncogenes.Claudio Franceschi (University of Bologna, Bologna, Italy) also described cross-talk between mitochondrial and nuclear genomes. He showed the