During the course of an individual’s lifetime, the DNA in their cells is constantly exposed to both endogenous and exogenous sources of stress that can induce DNA damage. Endogenous sources of stress include reactive oxygen species and reactive aldehydes; and exogenous sources include exposure to ultraviolet radiation, cigarette smoke, alcohol, and consumption of grilled foods. However, not every part of the human genome is equally susceptible to damage. Specific regions of the human genome, referred to as fragile sites (FS), are inherently more vulnerable to stress. Due to the unique characteristics governing FS, it is believed that these regions were evolutionarily designed to function as endogenous sensors or “first responders” to alert our cells when there is an adverse exposure that induces stress. The vulnerability of FS to stress has been collectively attributed to the repetitive sequence composition, their peculiar replicative features, and the presence of actively transcribed genes at these sites. Furthermore, since FS-associated gene transcription and replication programs are highly cell-type specific, the genomic locations classified as FS can vary significantly between different cell types. Maintenance of FS integrity is critical because most of the commonly expressed FS contain long tumor suppressor genes and proto-oncogenes that, when disrupted, can lead to cancer. Since FS instability is strongly implicated in the onset of tumorigenesis, elucidating the molecular and cellular mechanisms that ensure genome stability at these regions has been critical to understanding the pathophysiological consequences associated with the regions.

This application falls under the “blood cancers” classification of Fiscal Year 2020 Peer Reviewed Cancer Research Program Topic Area and focuses on the short-/long-term impact of environmental exposure to agents that induce mutations, predisposing one to cancer. Over the years, a number of precancerous states have been associated with defined hypermutable FS regions. In this application, we will be focusing on the precursor state for hematological malignancies, referred to as clonal hematopoiesis. Clonal hematopoiesis is a phenomenon in which the acquisition of somatic mutations at defined genomic regions confer a fitness advantage to hematopoietic stem cells that enables them to expand clonally. Here, using novel cellular systems and multidisciplinary approaches, we aim to evaluate a subset of genomic regions that are hotspots of somatic hypermutation in the hematopoietic lineage to determine whether they are putative “undiscovered fragile sites.”

Ultimate applicability of the research: Through this study, in addition to identifying genomic characteristics that predispose hypermutability at these regions, we will be able to get a better understanding of the mechanism(s) driving this phenotype. The results from this study will be of particular relevance to individuals displaying clonal hematopoiesis who are at high risk for hematological malignancies and secondary cardiovascular disease and inflammation.

Relevance to active-duty Service Members, Veterans, and other military beneficiaries: While clonal hematopoiesis is an age-related phenomenon, there have been numerous reports showing a significant correlation between lifestyle choices and job-related adverse environmental exposures (e.g., smoking, polychlorinated biphenyl, dioxins, polycyclic aromatic hydrocarbons, and asbestos) to accelerated clonal hematopoiesis development. For these reasons, this project is of particular relevance to active-duty Service Members, Veterans, and other military beneficiaries who currently are or have been on the front lines of toxic environmental exposures. Early and regular assessment of these active-duty Service Members, Veterans, and other military beneficiaries for clonal hematopoiesis-associated mutations by sequencing will enable health care professionals tremendously in monitoring at-risk individuals for hematological cancers that are easier to cure when detected early, and secondary prevention of cardiovascular disease. More importantly, depending on the nature and location of the mutations, this will help tremendously with early interventions. For these reasons, this study has tremendous potential to advancing the field of cancer research and patient care.