MITOCHONDRIAL BACKGROUND IN HPV POSITIVE INDIVIDUALS FROM THE PHILADELPHIA AREA

Disease has shaped human health and survival over evolutionary time. Understanding the ways in which past human adaptations have affected the health of contemporary populations may provide insight into the biological pathways that are targets for disease prevention and health intervention. After migration out of Africa, modern humans encountered a range of different environments and climate conditions that presented adaptive challenges. In the process, they underwent genetic diversification including changes in the mitochondrial DNA (mtDNA) sequence variation. Such variants may have allowed humans to adapt to cold and temperate conditions through functional genetic changes affecting cellular energetics. Different mutations in the mtDNA may further have predisposed humans to develop diseases affected by metabolism and oxidative stress, processes which are mediated by the mitochondria. In this regard, certain mitochondrial lineages have been associated with an increased risk of developing diseases such as diabetes, Parkinson’s disease, Alzheimer’s disease, and certain types of cancer, including cervical cancer. It is important to note that, while mitochondrial DNA variants can affect an individual’s disease risk, they are not the only factor involved in disease development. Environmental factors, lifestyle choices, and other genetic variants in the nuclear DNA may also play a role in disease etiology. In cervical cancer development, high- risk human papillomavirus (HPV) proteins directly interact with the mitochondria. HPV proteins promote DNA damage via increased reactive oxygen species (ROS) production and thus cancer cell transformation. These proteins also affect apoptosis of transformed cells leading to further cancer cell proliferation. These observations suggest that mitochondria are involved with HPV-induced malignancies. To improve our understanding of the role of mitochondrial background in cervical cancer development, I analyzed previously tested cervical swab samples from the Pathology Department at the Hospital of the University of Pennsylvania (HUP). These samples were anonymized and analyzed for mtDNA haplogroup and HPV type. In addition, data from medical records on age, pap cytology, smoking, self-identified race, clinical site, and income level were collected for each study participant. The results of this study confirmed that high risk types HPV-16 and -18 as well as smoking status were associated with the development of cervical precursor lesions. Despite these important observations, the sample size of the study was too small to confirm the role of mtDNA variants/haplogroups in the onset of cervical cancer in study participants. In light of these finding, I explore the insights, limitations, and possible directions of research with HPV and mtDNA based on the methodology used in this dissertation project. Future research with larger samples sizes may enhance our understanding of the relationship between mitochondrial background, cervical precancer development, and socio-demographic factors. It may further help to identify at risk groups as clinical targets toward which treatment measures may be taken to improve health and health equity in different human populations.