Grant Number:	5R03CA133907-02 Interpret this number
Primary Investigator:	Zhao, Hua
Organization:	Roswell Park Cancer Institute Corp
Project Title:	DNA Repair Capacity and Risk of Pre-Malignant Lesion in Lung Epithelium
Fiscal Year:	2009

DESCRIPTION (provided by applicant): This RO3 grant application is in response to NIH Small Grants Program for Cancer Epidemiology (PA-06- 294).Detecting pre-malignant lesions in central airway in high risk population has significant implication in decreasing lung cancer morbidity and mortality. However, the natural history of these lesions is unclear, especially for low grade lesions, such as metaplastia. Inflammation has been recognized as an important factor in lung carcinogenesis. Animal studies, as well as molecular epidemiological studies in humans, have provided evidence that the influx of neutrophils into the airways may be an important process linking inflammation with carcinogenesis. It is hypothesized that the genotoxicity of neutrophils, including induction of oxidative DNA damage through release of reactive oxygen species (ROS) and myeloperoxidase (MPO)-related metabolic activation of chemical carcinogens, is a crucial etiological factor in this carcinogenic response. There are extensive DNA repair systems that can correct DNA damage caused by ROS and MPO-related carcinogen activation before cell replication and mutation fixation. For instance, ROS-caused base damages are mainly repaired by base excision repair (BER) and nucleotide excision repair (NER); DNA adducts caused by MPO- related carcinogen activation are repaired by NER. However, DNA repair capacity (DRC) is substantially variable among individuals in the population, and suboptimal DRC of DNA damage might increase genomic instability and hence, increase risk of pre-malignant lesion and eventual lung cancer development. Although inflammation appears to be important in the nature history of lung pre-malignant lesions, so far there is no study to investigate whether DRC of inflammation caused DNA damage is associated with development of pre- malignant lesions in lung epithelium. Therefore, we propose this study to test the hypothesis that DRC of inflammation caused DNA damage may predict pre-malignant lesion development in lung epithelium. In this study, we will use samples and questionnaire data from a cohort of lung cancer high risk patients underwent autofluorescent brochoscopy (AFB) screening at the Lung Cancer Screening Clinic at the Roswell Park Cancer Institute in Buffalo NY between the years of 1998 } 2006. In Specific Aim 1, we will determine the role of DRC of ROS caused DNA damage in development of pre-malignant (metaplastic and dysplastic) lesions in lung epithelium. To achieve this goal, we will apply mutagen sensitivity assay to quantify levels of H2O2 induced 8-OH-dG in lymphocytes reflecting systemic BER capacity. Then, we will correlate levels of H2O2 induced 8-OH-dG in lymphocytes with baseline status pre-malignant (metaplastic and dysplastic) lesions in lung epithelium in individuals at high risk of lung cancer. In Specific Aim 2, we will determine the role of DRC of DNA adducts caused by MPO-related carcinogen activation in development of pre-malignant (metaplastic and dysplastic) lesions in lung epithelium. To achieve this goal, we will apply host cell reactivation (HCR) assay to quantify DRC of BPDE induced DNA adducts in plasmid pGL-3-luc in lymphocytes reflecting systemic NER capacity. Then, we will correlate levels of DRC of BPDE induced DNA adducts in lymphocytes with baseline status pre-malignant (metaplastic and dysplastic) lesions in lung epithelium in individuals at high risk of lung cancer. Project Narrative Detecting pre-malignant lesions in central airway in high risk population has significant implication in decreasing lung cancer morbidity and mortality. However, the natural history of these lesions is unclear, especially for low grade lesions, such as metaplasia. Inflammation has been recognized as an important factor in lung carcinogenesis. Animal studies, as well as molecular epidemiological studies in humans, have provided evidence that the influx of neutrophils into the airways may be an important process linking inflammation with carcinogenesis. It is hypothesized that the genotoxicity of neutrophils, including induction of oxidative DNA damage through release of reactive oxygen species (ROS) and myeloperoxidase (MPO)-related metabolic activation of chemical carcinogens, is a crucial etiological factor in this carcinogenic response. There are extensive DNA repair systems that can correct DNA damage caused by ROS and MPO-related carcinogen activation before cell replication and mutation fixation. DNA repair capacity (DRC) is substantially variable among individuals in the population, and suboptimal DRC of DNA damage might increase genomic instability and hence, increase risk of pre-malignant lesion and eventual lung cancer development. Although inflammation appears to be important in the nature history of lung pre-malignant lesions, so far there is no study to investigate whether DRC of inflammation caused DNA damage is associated with development of pre- malignant lesions in lung epithelium. Therefore, we propose this study to test the hypothesis that DRC of inflammation caused DNA damage may predict pre-malignant lesion development in lung epithelium. The study will further our understanding of the genetic events leading to the development of pre-malignant lesions; explore the genetic basis of inflammation and pre-malignant lesions; and eventually elucidate the multi-step of lung carcinogenesis. The information from this study will also provide a means of identifying a subgroup that are most likely to develop lung cancer. Such individuals may then be targeted for specific intervention programs such as chemoprevention and dietary modification.





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