Exposure Specific Mutation In Critical Target Genes

关键靶基因的暴露特异性突变

• 批准号: 6535072
• 负责人: JACK A TAYLOR
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6535072
• 关键词: biopsy; bladder neoplasm; bronchoscopy; cancer risk; chemical carcinogen; chemical carcinogenesis; clinical research; early diagnosis; endoscopy; environment related neoplasm /cancer; environmental exposure; fluoroscopy; gene environment interaction; gene mutation; human subject; lung neoplasms; molecular cloning; molecular oncology; neoplasm /cancer diagnosis; neoplasm /cancer genetics; neoplastic process; polymerase chain reaction; preneoplastic state; single strand conformation polymorphism; southern blotting; tumor suppressor genes; biopsy; bladder neoplasm; bronchoscopy; cancer risk; chemical carcinogen; chemical carcinogenesis; clinical research; early diagnosis; endoscopy; environment related neoplasm /cancer; environmental exposure; fluoroscopy; gene environment interaction; gene mutation; human subject; lung neoplasms; molecular cloning; molecular oncology; neoplasm /cancer diagnosis; neoplasm /cancer genetics; neoplastic process; polymerase chain reaction; preneoplastic state; single strand conformation polymorphism; southern blotting; tumor suppressor genes

Aims: Tumors initiated in laboratory rodents by different chemical carcinogens can have distinctive patterns of oncogene and tumor suppressor gene mutation, suggesting that these and other genes may be critical targets of environmental carcinogens. A longstanding area of my research has been to test the hypothesis that environmental exposures produce specific patterns of gene mutation in human tumors. Such patterns can be used both to identify critical target genes and to suggest mutational mechanisms by which an environmental agent causes cancer. If specific carcinogens produce characteristic patterns of gene mutation in tumors, the detection of those patterns would be a powerful tool in studies of environmental risk and for use in prevention and early diagnosis. In a related effort, we have designed a new study to test the hypothesis that exposure correlates with the pattern of mutation in premalignant and normal lung tissues and that such mutations may have prognostic significance for lung cancer development. We are using the Lung Imaging Fluorescent Endoscope (LIFE), a newly developed bronchoscopy technique that is a very sensitive method for detecting premalignant lesions and carcinoma in situ (CIS). CIS and premalignant lesions in the lung are not resected by biopsy and there is no recognized standard-of-care treatment for such lesions. Current practice is to follow them without intervention. This will be the first systematic study to follow prospectively the natural development of lung cancer precursor lesions and CIS over time with sequential biopsies. Detection of molecular defects in such tissues may allow us to identify mutational patterns related to exposure and to provide better estimates of lung cancer risk, progression, and prognosis. Procedures and techniques: Epidemiological studies and PCR, SSCP, sequencing, cloning, and Southern blotting; Lung Imaging Fluorescent Endoscope, bronchoscopy Accomplishments: We examined exposure-specific mutations of ras and p53 in epidemiologic studies of 1) aflatoxin and hepatatis B virus in hepatocellular carcinoma, 2) smoking, occupation, and metabolism gene polymorphisms in bladder cancer, 3) organochlorines and diabetes in pancreatic cancer. We have extended our work on multiple mutations in bladder cancer and find frequent alternative splicing of DNA polymerase b. We have developed sensitive techniques for detecting mutations in tumor tissues and established methods for working with the small and degraded samples often available for epidemiology studies. LIFE Study. We have established a prospective study of people at high risk of developing lung cancer that is designed to test whether molecular changes in normal and preneoplastic bronchial epithelium are correlated with exposure or neoplastic progression. We have established techniques for microdissection and LOH analysis from small biopsy samples and for bronchial epithelial cell

目的：不同化学致癌物在实验室啮齿动物中引发的肿瘤可以具有独特的癌基因和肿瘤抑制基因突变的模式，这表明这些和其他基因可能是环境致癌物的关键靶标。我的研究的一个长期以来一直是检验以下假设：环境暴露会在人类肿瘤中产生特定的基因突变模式。这种模式既可以用来识别关键靶基因，又建议通过环境剂引起癌症的突变机制。如果特定的致癌物在肿瘤中产生基因突变的特征模式，那么对这些模式的检测将是对环境风险以及用于预防和早期诊断的使用的强大工具。在相关的工作中，我们设计了一项新的研究，以检验以下假设：暴露与前态和正常肺组织中突变的模式相关，并且这种突变可能对肺癌发育具有预后意义。我们使用的是肺成像荧光内窥镜（LIFE），这是一种新开发的支气管镜技术，是一种非常敏感的方法，用于检测原位预先病变和原位癌（CIS）。肺中的顺式病变和预临床病变未通过活检切除，并且对于此类病变没有公认的护理标准治疗。当前的做法是在没有干预的情况下跟随他们。这将是首次遵循肺癌前体病变的自然发育和随着时间的流逝的系统研究。这种组织中分子缺陷的检测可能使我们能够识别与暴露有关的突变模式，并更好地估计肺癌风险，进展和预后。程序和技术：流行病学研究和PCR，SSCP，测序，克隆和南部印迹；肺部成像荧光内窥镜，支气管镜检查的成就：我们在流行病学研究中检查了RAS和p53的暴露特异性突变。 癌症。我们已经扩展了有关膀胱癌多重突变的工作，并发现了DNA聚合酶b的频繁替代剪接。我们开发了用于检测肿瘤组织突变的敏感技术，并建立了与通常用于流行病学研究的小型和降解样品一起工作的方法。生活研究。我们已经建立了一项前瞻性研究，对患有肺癌的高风险的人进行了前瞻性研究，该研究旨在测试正常和肿瘤支气管支气管上皮的分子变化是否与暴露或肿瘤进展相关。我们已经建立了从小型活检样品和支气管上皮细胞进行显微解剖和LOH分析的技术