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：由不同化学致癌剂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，表明这些基因和其他基因可能是环境致癌剂的关键靶标。我的一个长期研究领域是检验环境暴露会在人类肿瘤中产生特定基因突变模式的假设。这种模式既可用于识别关键靶基因，又可用于提示环境因素导致癌症的突变机制。如果特定的致癌物在肿瘤中产生特征性的基因突变模式，那么对这些模式的检测将成为环境风险研究以及预防和早期诊断的有力工具。在一项相关工作中，我们设计了一项新研究来检验以下假设：暴露与癌前和正常肺组织的突变模式相关，并且此类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，是检测癌前病变和原位癌 (CIS) 的非常灵敏的方法。肺部原位癌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护理标准治疗方法。目前的做法是遵循它们而不进行干预。这将是第一个系统研究，通过连续活检前瞻性地跟踪肺癌前体病变和 CIS 随着时间的推移的自然发展。检测此类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 Southern 印迹；肺成像荧光内窥镜、支气管镜检查 成就：我们在 1) 肝细胞癌中的黄曲霉毒素和乙型肝炎病毒，2) 膀胱癌中的吸烟、职业和代谢基因多态性，3) 有机氯的流行病学研究中检查了 ras 和 p53 的暴露特异性突变和胰腺癌中的糖尿病。我们扩展了对膀胱癌多种突变的研究，并发现了 DNA 聚合酶 b 的频繁选择性剪接。我们开发了检测肿瘤组织突变的敏感技术，并建立了处理通常可用于流行病学研究的小样本和降解样本的方法。生活研究。我们对罹患肺癌的高风险人群进行了一项前瞻性研究，旨在测试正常和癌前支气管上皮的分子变化是否与暴露或肿瘤进展相关。我们已经建立了对小活检样本和支气管上皮细胞进行显微切割和 LOH 分析的技术