Unraveling Early Cancer Dynamics for Targeted Cancer Prevention

Abstract My research is focused on identifying the earliest stages in cancer development. This information can be used to determine who is at the highest risk of getting cancer and to develop interventions that stop cancer from forming. Central to our work are mutations, which are the root cause of cancer. Each cell in our body has a copy of our DNA, or genome, which is composed of approximately 3 billion nucleotides, or “letters.” Just like a recipe, our DNA holds instructions for making molecules and directs cellular functions. Mutations refer to changes in the DNA that can cause errors in the “molecular recipe”, resulting in cellular dysfunction and the subsequent development of cancer. In our research, we use advanced computational and statistical methods to analyze some of the largest genomic data sets available. Our research has shown that mutations are not exclusive to cancer but rather are present across normal tissues in the body. By studying mutations in normal tissues, we have identi?ed DNA changes correlated with a high risk of developing leukemia. We have also found elevated levels of large mutations in the airways of smokers and novel inherited factors that increase mutations and the risk of cancer. In our studies, we ?nd that mutational patterns are not the same across the body. For example, chromosome 1q copy number mutations a?ecting 5% of the genomic DNA are common in normal breast tissues but are not common in other parts of the body. 1q mutations are the most common mutation found in breast cancers (>50%). We are working collaboratively with the director of the largest biobank of normal breast tissue to determine if 1q mutations are more common in the breast tissues of women who developed breast cancer after tissue donation. Such a biomarker of breast cancer risk would help identify women who should be referred to a breast cancer prevention clinic. Recent studies show that radon, an odorless radioactive gas, which is the leading cause of lung cancer in nonsmokers, may also increase the risk of blood and breast cancer. Half of the homes in Kentucky have radon levels above what is considered safe, but little is known about the impact of radon on mutations in human tissues. Over the next year, with the support of the Markey Women Strong initiative, we will investigate the link between radon and mutations using existing genomic data from 1,900 Kentucky residents to determine if large mutations (linked to the highest risk of blood cancer) are more common in people living in high radon regions. In parallel, we are working with a collaborator in the department of physiology to implement cutting-edge molecular and computational methods for in-depth characterization of mutational signatures from blood. Our goal is to identify a mutational signature associated with radon exposure that can serve as a blood-based biomarker for use in clinical testing. A biomarker of radon exposure would help identify non-smokers needing routine lung cancer screening and be especially valuable because it could track lifetime exposure—including childhood—across moves, when most people don’t know their home’s radon levels. Our long-term research goal is to identify biomarkers indicating high cancer risk and use these to refer people to high-risk clinics and to identify chemo-preventive agents and lifestyle interventions that decrease cancer risk, sparing people from ever having to hear the words “you have cancer.”