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

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能具有独特的癌基因和抑癌基因突变模式，这表明这些和其他基因可能是环境致癌物的关键靶点。我的一个长期研究领域是检验环境暴露在人类肿瘤中产生特定基因突变模式的假设。这种模式既可以用来识别关键的靶基因，也可以用来提示环境因子导致癌症的突变机制。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研究环境风险以及用于预防和早期诊断的有力工具。在一项相关的研究中，我们设计了一项新的研究来检验这一假设，即暴露与癌前病变和正常肺组织中的突变模式相关，并且这种突变可能对肺癌的发展具有预后意义。我们正在使用肺成像荧光内窥镜（LIFE），这是一种新开发的支气管镜检查技术，是一种非常敏感的检测癌前病变和原位癌（CIS）的方法。肺部CIS和癌前病变不能通过活检切除，并且对于此类病变没有公认的标准治疗。目前的做法是在不干预的情况下遵循这些原则。这将是第一个系统的研究，前瞻性地遵循自然发展的肺癌前体病变和CIS随着时间的推移与顺序活检。检测这些组织中的分子缺陷可能使我们能够识别与暴露相关的突变模式，并提供更好的肺癌风险，进展和预后估计。程序和技术：流行病学研究和PCR、SSCP、测序、克隆和Southern印迹;肺成像荧光内窥镜、支气管镜检查成就：我们在以下流行病学研究中检测了ras和p53的特异性突变：1）肝细胞癌中的黄曲霉毒素和肝细胞B病毒，2）膀胱癌中的吸烟、职业和代谢基因多态性，3）胰腺癌中的有机氯和糖尿病。我们已经扩展了我们在膀胱癌中的多突变研究，发现了DNA聚合酶B频繁的选择性剪接。我们已经开发了检测肿瘤组织突变的灵敏技术，并建立了用于流行病学研究的小样本和降解样本的方法。生命研究。我们已经建立了一个前瞻性研究的人在高风险的发展肺癌，旨在测试是否在正常和癌前支气管上皮细胞的分子变化与暴露或肿瘤进展相关。我们已经建立了小活检样本和支气管上皮细胞的显微切割和洛杂合性缺失分析技术