SUSCEPTIBILITY TO MOLECULAR ALTERATION: EPITHELIAL CELLS

K23指导患者导向研究奖的目标是获得癌症遗传学、分子流行病学和患者导向研究方面的概念和技术技能，并随后应用这些技能来提高肺癌患者或有患肺癌风险患者的生存率。这些目标将通过包括正规教育、以患者为导向的研究和临床活动在内的综合计划来实现。教育计划将包括分子遗传学，临床流行病学和临床研究课程。定期参加与癌症和分子遗传学有关的国家会议和专题讨论会将是教育计划的重要组成部分。临床活动将以肺癌为重点。这个以病人为导向的研究项目的长期目标是确定导致妇女肺癌发病率增加的环境和遗传因素。最近的统计趋势和病例对照研究表明，接触类似烟草的女性比男性更容易患肺癌。本研究项目的目标是确定上皮细胞中DNA暴露于致癌物（DNA加合物）的生物标志物和影响的生物标志物（杂合性丧失和p53突变）是否与女性肺癌易感性有关。该项目的具体目标是确定女性中上皮细胞DNA加合物、LOH和p53突变的程度是否与接触类似烟草的男性不同，并确定性别、遗传多态性和饮食对这些接触和影响生物标志物之间关系的影响。本研究将评估60名女性和60名男性中年吸烟者。生物标志物将在所有个体的肺、膀胱和口咽部上皮细胞中进行评估。CYP1A1和GSTM1的多态性与维生素和类胡萝卜素的膳食摄入量将被表征。这些实验将提供遗传和环境因素如何影响女性肺癌易感性的重要信息。这些机制的定义可能允许在发展为肺癌的风险增加个体的前瞻性识别。

The objectives for this K23 Mentored Patient Oriented Research Award are to acquire conceptual and technical skills in cancer genetics, molecular epidemiology, and patient oriented research and subsequently to apply these skills to improve the survival of patients with lung cancer or at risk for developing lung cancer. These goals will be achieved through a comprehensive program that includes formal education, patient oriented research and clinical activities. The educational program will include courses on molecular genetics, clinical epidemiology and clinical research. Regular participation in national meetings and symposia related to cancer and molecular genetics will be an essential part of the educational program. The clinical activities will be focused on lung cancer. The long-term objective for the patient oriented research project is to identify the environmental and genetic factors that are responsible for the increased incidence of lung cancer in women. Recent statistical trends and case-control studies suggest that women are more susceptible to lung cancer than men with similar tobacco exposure. The goal for this research project is to determine if biomarkers of DNA exposure to carcinogens (DNA adducts) and biomarkers of effect (loss of heterozygosity and p53 mutations) in epithelial cells are involved in lung cancer susceptibility in women. The specific aims of the project are to determine if the extent of epithelial cell DNA adducts, LOH, and p53 mutations in women is different than in men with similar tobacco exposure and to determine the effect of gender, genetic polymorphisms, and diet on the relationships among these biomarkers of exposure and biomarkers of effect. This study will evaluate 60 female and 60 male middle aged smokers. Biomarkers will be evaluated in epithelial cells from the lung, bladder and oropharynx from all individuals. Polymorphisms of CYP1A1 and GSTM1 and dietary intake of vitamins and carotenoids will be characterized. These experiments will provide important information on how genetic and environmental factors are involved in lung cancer susceptibility in women. The definition of these mechanisms may allow the prospective identification of individuals at increased risk for developing lung carcinoma.