Although early detection and removal of colorectal adenomas, the precursors of most colorectal cancers, has significantly reduced morbidity and mortality due to colorectal cancer, the disease remains the second leading cause of cancer mortality in the United States. There is increasing evidence that oxidative stress plays an important role in the pathogenesis of colorectal cancer. We recently found that increased circulating concentrations of oxidative stress biomarkers are associated with increased colorectal adenoma risk. Mitochondria (Mt) are the predominant source of intracellular reactive oxygen species (ROS) and a major cause of endogenous oxidative stress. Mitochondrial variations (mitochondrial DNA (mtDNA) copy number and mitochondrial polymorphisms) have been associated with increased ROS production. Despite the central role for mitochondria in ROS production, their role in pathogenesis of colorectal adenomas has not been evaluated. We hypothesize that mtDNA copy number and germline variations in the mitochondrial genome will be associated with colorectal adenoma risk. We propose to evaluate this hypothesis by measuring mtDNA copy number using real time polymerase chain reaction and genotyping mitochondrial tagging single nucleotide polymorphisms (tagSNPs) and D-loop polymorphisms in 392 colorectal adenoma cases and 565 controls collected from three methodologically very similar, colonoscopy-based case-control studies of incident, sporadic colorectal adenomas. We will use unconditional logistic regression to analyze the association between mtDNA copy number, mitochondrial polymorphisms and colorectal adenoma risk. This innovative epidemiologic study seeks to translate our understanding of mitochondrial biology into discovery of novel mitochondrial biomarkers that can inform strategies for the primary prevention of colorectal adenoma. Findings from this exploratory study will provide preliminary data to design a prospective study with adequate sample size to confirm the findings from this study and comprehensively evaluate the role of mitochondria in colorectal cancer etiology.
This application aims to evaluate the association between mitochondrial variants (mitochondrial DNA copy number and mitochondrial polymorphisms) and risk of colorectal adenoma is an existing dataset of 392 colorectal adenoma cases and 565 controls. The long-term goal of the proposed project is to further our understanding of the complex interactions between genetic and environmental/lifestyle factors that affect risk for incident, sporadic colorectal cancer.