Mitochondrial DNA Copy Number, Insulinemic Potential of Lifestyle, and Colorectal Cancer

Abstract

Because colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer death in the US, identifying biomarkers that might inform disease prevention and early diagnosis is of great public health importance. Mitochondria are key cytoplasmic organelles containing an independent genome, i.e., mitochondrial DNA (mtDNA). It has been increasingly recognized that mtDNA copy number (mtDNAcn) is a biomarker for mitochondrial function and cellular oxidative stress. To date, the few studies that have assessed associations between mtDNAcn and CRC outcomes have yielded inconsistent findings. Further, no epidemiologic study has examined the relationship between insulinemic potential of lifestyle and mtDNAcn. Therefore, in this dissertation, three studies were conducted using data from the Nurses’ Health Study and the Health Professionals Follow-Up Study. First, the association between pre-diagnostic leukocyte mtDNAcn and CRC risk was studied in a nested casecontrol study (324 cases/658 controls). Lower mtDNAcn was significantly associated with increased risk of CRC and proximal colon cancer. That inverse association remained significant among individuals with ≥ 8 years’ follow-up since blood collection, suggesting that mtDNAcn might serve as a long-term predictor of CRC risk. Second, possible associations of pre-diagnostic mtDNAcn with overall and CRC-specific survival were examined among 587 CRC patients. MtDNAcn was not significantly associated with survival overall or in subgroups by cancer location, grade, or stage. Among current smokers, there was an inverse association between one standard deviation (SD) decrease in mtDNAcn and increased overall death risk. Among patients diagnosed at or before 70.5 years of age and those with anti-inflammatory diets, reduced mtDNAcn was associated with lower CRC-specific death risk. Lastly, the cross-sectional association between empirical lifestyle index for hyperinsulinemia (ELIH) and mtDNAcn was investigated among 2,835 subjects without major chronic diseases (cancers, diabetes, and cardiovascular diseases). A significant inverse association was found: least-squares means ± SD of mtDNAcn z-score decreased dramatically across ELIH quintiles. Overall, the findings from this dissertation will contribute to the evaluation of mtDNAcn as a potential biomarker for CRC risk and prognosis, and inform future interventions designed to reduce the insulinemic potential of lifestyle factors to preserve mitochondrial function.