Pre-pilot A: Mitochondrial DNA Repair Capacity in Colorectal Cancer: A Case-Control Study
Co-Investigators
Randa El-Zein, Ph.D., Associate Professor, Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
Carlos Torres, Ph.D., Assistant Professor, Department of Physiology, University of Puerto Rico - Medical Sciences Campus, Rio Piedras, Puerto Rico
The elucidation of the genetic defects in cancer prone diseases such as xeroderma pigmentosum and hereditary nonpolyposis colorectal cancer have established that diminished DNA repair capacity leads to cancer. In addition to nuclear DNA (nDNA), mitochondrial DNA (mtDNA) harbors lesions induced by reactive oxygen species (ROS) generated as by-products of oxidative phosphorylation or by xenobiotic agents. Unrepaired mtDNA lesions can lead to mutations that can alter energy production, ion homeostasis and apoptosis, processes in which mitochondria play a central role. These changes in mitochondrial physiology lead to increased genomic instability and cancer. Mutations in mtDNA have been detected in many forms of cancer, including colorectal cancer. The increased mtDNA mutations in colorectal cancer suggest that DNA repair may be limiting in this type cancer. However, there is no direct evidence that links mtDNA repair capacity with the development of colorectal cancer. Base excision repair (BER) is the main DNA repair pathway used in the repair of ROS-induced lesions. Strong evidence shows that mitochondria have the capacity to carry on BER to repair mtDNA damage. Therefore, the type of lesions that may accumulate in colorectal cancer could be due to oxidative stress. The long-term goal of this project is to determine the role of mtDNA repair in colorectal cancer.
Specific Aims
- Determine the experimental variability in the QPCR assay in order to perform a power analysis to determine the number of case patients and control subjects needed for significant statistics.
Completion of this aim will allow us to:
- Evolve into a pilot project in which we will determine the mtDNA repair capacity of colon cancer patients and healthy control subjects
- Develop a full project in which we will increase the number of case patients and control subjects to reach the statistical significant number defined in the pilot studies
- Obtain a baseline of mtDNA repair capacity in both the general population and in colorectal cancer patients.
This study will be expanded, by means of competitive R-type awards, to determine risk factors (such as age, smoking status, polymorphisms in DNA repair enzymes, etc.) that can influence mtDNA repair capacity and therefore cancer risk.