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Genome-wide mapping of smoke-induced DNA damage and mutation

Institution: Beckman Research Institute of the City of Hope
Investigator(s): Ahmad Besaratinia, Ph.D., M.P.H.
Award Cycle: 2011 (Cycle 20) Grant #: 20XT-0116 Award: $80,381
Subject Area: Cancer
Award Type: Exploratory/Developmental Award

Initial Award Abstract
LUNG cancer continues to remain a primary focus of research on the adverse health effects of smoking. The importance of this field of research is due to the graveness of this disease, which is often diagnosed at late stages with poor response to the available treatment options, thus, translating into high mortality. Although the initial flurry of research has unraveled many aspects of smoke-derived lung cancer, the exact underlying mechanism of this malignancy awaits further delineation. Today, the gaps in mechanistic knowledge of smoke-associated lung cancer constitute the main obstacle in the management of this highly lethal disease. Determining the underlying mechanism of lung cancer development can help elucidate the sequential chain of events leading to this malignancy. Mechanistically establishing the chronology of events, which occurs in lung cancer, can help identify unique biological markers that can be used for early detection of this disease, as well as for prognosis and evaluation of its treatment strategies.

The studies proposed in this application are the first attempt to intercept the continuum of exposure to cigarette-smoke and lung cancer development at different intervals to gain insights, on a genome-wide scale, into the chain of events, which is initiated by exposure to cigarette smoke and ultimately led to tumor formation. These intervals pertain to a driving force of cancer development, namely DNA damage-derived mutagenesis (genotoxicity), which occurs frequently and early in the process of lung cancer development. Using a well-defined validated cell culture model system and under strictly controlled experimental conditions, we will chronically treat human lung cells with biologically relevant doses of cigarette smoke, and subsequently investigate the induced genotoxic effects using the state-of-the-art next generation sequencing and DNA footprinting technologies together with mutagenesis assays. Our herein proposed investigations will elucidate the underlying mechanism of cigarette smoke-induced genotoxicity, which will, in turn, help devise future strategies for early diagnosis, prognosis, treatment, and prevention of lung cancer. Of significance, our proposed studies are the first attempt to investigate the genotoxic effects of a cancer-causing agent on a genome-wide scale using the state-of-the-art high throughput next generation sequencing technologies, which will pave the way for future genome-wide studies on other known/suspected carcinogens. Worldwide, our laboratory is one of the few, where mechanistic research on cancer causation can be performed both on a genome-wide scale and locus-specifically.

Our proposed project is highly relevant to the mission of Tobacco-Related Disease Research Program (TRDRP) because it can provide invaluable mechanistic information on lung cancer development, which can be used for, e.g., evaluation of the efficiency of preventive strategies in at risk; populations (i.e., smokers), assessment of the efficacy of various treatment options in lung cancer patients, or development of unique biological markers for human biomonitoring purposes, e.g., to assess lung cancer risk in relation to secondhand smoke exposure, i.e., in individuals with known exposure to secondhand smoke, such as smokers'; spouses and children.