Abstract
The elucidation of the genetic defects in cancer prone diseases such as Xeroderma pigmentosum and hereditary nonpolyposis colorectal cancer have established that diminished nuclear DNA (nDNA) repair capacity leads to cancer. In addition to nDNA, mitochondrial DNA (mtDNA) preferentially harbors lesions induced by endogenous reactive oxygen species (ROS) or by xenobiotic agents. If these lesions are left unrepaired, they may lead to mutagenesis, which may be deleterious to mitochondrial function. Mutations in mtDNA have been described in most cancers including colorectal cancer. The functional significance of these mutations is not totally understood but mutations in some mitochondrial genes are associated with increased aerobic glycolysis and growth promotion in cancer cells. In addition, dysfunctional mitochondria are more prone to produce ROS that in turn can inflict further damage to both mitochondrial macromolecules and nDNA. ROS induce a variety of DNA lesions that include base modifications, abasic sites, and strand breaks. These lesions are mainly repaired by base excision repair (BER). BER is active in mitochondria and is considered the main mechanism by which mtDNA damage is repaired. We hypothesize that decreased mtDNA repair capacity is a risk factor for the development of cancer, particularly cancers in which inflammation and oxidative stress are critical components in tumor development and progression, such as colorectal cancer. Thus, increased levels of mtDNA damage could reflect decreased mtDNA repair capacity. The purpose of this work is to determine if mtDNA damage levels in peripheral blood mononuclear cells (PBMC) can be used as a biomarker of cancer susceptibility of colorectal cancer. For this purpose we applied a gene-specific PCR-based technique (QPCR) that can detect with high sensitivity a variety of DNA lesions such as base modifications, abasic sites, and strand breaks, among others. The results of our preliminary experiments indicate that mtDNA from colorectal cancer patients harbor more lesions than mtDNA from healthy control subjects. These results suggest that mtDNA damage may be used as biomarker for colorectal cancer susceptibility. Experiments are in progress to increase the sample size and the statistical power of this study. Sponsored by 5U54CA096297-07.
Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A56.
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