Mitochondrial DNA Copy Number, Lifestyle and Cancer Risk
CitationMeng, Shasha. 2015. Mitochondrial DNA Copy Number, Lifestyle and Cancer Risk. Doctoral dissertation, Harvard T.H. Chan School of Public Health.
AbstractMitochondria are membrane-bound organelles found in the cytoplasm of almost all eukaryotic cells. Their main functions include energy metabolism, free radical production, calcium homeostasis and apoptosis. Located closely to the source of reactive oxidative stress (ROS) production, Mitochondrial DNA (mtDNA) is extremely susceptible to oxidative damage due to its absence of protective histones, the lack of introns and a scarcity of the efficient DNA repair mechanisms. Associations between leukocyte mtDNA copy number (mtCN) and various oxidative stress related health outcomes have been demonstrated in multiple prospective studies. MtCN has also been suggested to be a contributor to many cancer types. These pieces of evidence suggest that mtCN in leukocytes may serve as a candidate biomarker for oxidative stress related general health outcomes. In this work, we determined associations between mtCN and skin cancer as well as lung cancer risk by case-control studies nested within the Nurses’ Health Study (NHS) and the Health Professional Follow-Up Study (HPFS). Furthermore, we examined relationships between various oxidative stress generating factors (age, smoking, physical activity, body anthropometric indices, weight change and alcohol consumption) and mtCN among women using controls from the previous two studies. Relative mtCN in peripheral blood leukocytes (PBL) was measured by quantitative PCR (qPCR)-based assay and covariates were collected by biannually updated questionnaires. Our results indicate that obesity and weight gain are associated with lower mtCN. Moreover, mtCN may be more sensitive to obesity, while telomere length reflects aging better. In terms of cancer risks, women with low mtCN are more likely to develop skin cancer and the increased melanoma risk associated with low mtCN is more apparent among women with low constitutional risk or high UV exposure history. Although mtCN was not significantly associated with lung cancer risk, current smokers might be more susceptible for the disease when mtCN first starts to decrease.
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