Application of Genomic and Epigenomic Methods to Understand Environmental and Dietary Factors in Carcinogenesis.

Abstract

Sporadic cancers comprise the vast majority of diagnosed cancer cases, many with a largely environmental etiology. The mechanisms by which specific environmental factors influence cancer risk, however, remain widely uncharacterized. Because sporadic cancers are diagnosed later in life, many incident cancer studies poorly quantify previous exposures or utilize methodologies that may not be appropriate for the study of cancer initiation or prevention. Developing novel methods of studying the role of nutrition and the environment in carcinogenesis will provide essential insight towards the prevention, early identification, and treatment of cancer. Incorporating novel culture methods, including primary tissue culture, will allow for the study of specific and relevant normal cell populations, including stem cells, that may be particularly sensitive to environmental and nutritional factors. The overarching goal of this dissertation was to develop and apply novel statistical and experimental methods to characterize the roles of nutrition and the environment in carcinogenesis and cancer prevention, with a focus on epigenetic change. In Chapter 2, comprehensive epidemiological and clinical information were paired with DNA methylation profiling of head and neck tumors to identify significant differences in tumor DNA methylation in chemically induced or human papillomavirus induced tumors. In Chapter 3, data on average dietary intake was paired with tumor epigenetic measurements to identify that a head and neck cancer patient’s diet in the year before diagnosis can significantly affect tumor epigenetic profiles, providing a potential mechanism by which diet affects disease prognosis. In Chapter 4, normal human breast stem cells from reduction mammoplasty tissue were treated with the putatively cancer prevention compounds curcumin and piperine, and a genome-wide screen was conducted to identify the stem cell specific changes induced by these compounds. The results and conclusions presented here reflect the utility of the application of these methods, from cancer molecular epidemiology to normal human in vitro stem cell culture, to understand the role of the environment in cancer.PhDEnvironmental Health SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/109055/1/colacino_1.pd