Bridging Epigenomics and Patient Data to Detect Enhanceropathies in Cancer
Abstract
Scientific Objective and Rationale Research studies involving Vietnam Veterans have reported that Veterans who were exposed to chemical herbicides such as Agent Orange have a higher than average frequency of developing lymphoma and other blood related cancers. Some studies have drawn a relationship between different levels of chemical exposure and cancer; however, not all Veterans who were exposed actually develop the disease. For the subset of those who have developed these cancers, it has been found that, as with many other complex diseases, treatment is difficult due to a wide and variable set of clinical symptoms and outcomes. We will explore how genetics play a role in an individual’s response to military risk factors associated with cancer, including (1) cancer susceptibility – why does one develop (or not develop) cancer?, and (2) cancer treatments – why does one respond (or not respond) to chemotherapy? Until recently, cancer genetic studies have largely focused on identifying so-called “coding mutations.” These mutations are genetic errors that directly impact a gene’s ability to produce functional proteins, which play key roles in normal cellular function. However, potential “coding mutations” account for less than 2% of the DNA that makes up the genome, thus failing to explain a majority of the genetic component of cancer susceptibility. Instead, recent studies suggest that as much as 80% of disease-associated genetic errors are enriched in “noncoding” parts of the gene, which are regulatory regions of the genome and function to control how and when a gene is turned on or off to make a protein. We find that the primary challenge to identify and study disease-causing “non-coding mutations” is that, compared to “coding mutations,” they cover a much larger area of the genome, which can be likened to the act of finding needles in a haystack. The objective of this proposal is to identify the genetic determinants of disease susceptibility and treatment response that are frequently found in the non-coding regulatory regions of the genome. We will integrate gene regulation data with large-scale patient genome data and Electronic Medical Record (EMR) data to identify and characterize novel genetic markers of lymphoma and blood cancers. Based on our preliminary work and our established expertise, we are confident that we will be able to accomplish our goals within the proposed 2-year timeline. Ultimate Applicability of the Research Upon the successful completion of the proposed research, we expect our approach to accelerate the discovery and characterization of gene regulatory contributions to the molecular pathology of lymphoma and leukemia, uncovering new druggable gene targets, ultimately providing patients with a wider range of potential treatment options and better outcomes. We aim to demonstrate an association of non-coding mutations with cancer patient diagnoses, and with an established analytical framework of genetics and medical records, this approach will be broadly applicable to detect new susceptibility mutations in other types of cancer that military personnel encounter. Fiscal Year 2019 Peer Reviewed Cancer Research Program Focus Area By identifying new genetic risk mutations associated with lymphoma and blood cell cancers, this proposal will address military relevant environmental risk factors associated with cancer (e.g., ionizing radiation, chemicals, infectious agents, environmental carcinogens, and stress).
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010522
Entities
People
- Emily C. Hodges
Organizations
- United States Army
- Vanderbilt University