Mustard Gas Exposure and Carcinogenesis of the Lung

芥子气暴露与肺部致癌

• 批准号: 7262617
• 负责人: CHARLES A. GIARDINA
• 金额: $ 13.36万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-18 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7262617
• 关键词: Acute; Appendix; CDKN1A gene; Carcinogens; Characteristics; Chemical Weapons; Chronic; Chronic Disease; Clinic; Control Groups; DNA; Data Set; Development; Disease; Employment; Etiology; Evaluation; Exposure to; Eye; Fingerprint; Frequencies; Gene Activation; Gene Mutation; Gene Targeting; Genetic; Genetic screening method; Health; Hemoptysis; Human; Individual; Iran; Iraq; Legal; Lesion; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Military Personnel; Molecular; Molecular Analysis; Mustard; Mustard Agent; Mustard Compounds; Mustard Gas; Mutagens; Mutate; Mutation; Nature; Nucleic Acids; Occupational Exposure; Organophosphates; Paraffin Embedding; Pathology; Pattern; Population; Positioning Attribute; Protein p53; Proteins; Sampling; Sequence Analysis; Skin; Staging; Stream; Symptoms; TP53 gene; Testing; Tissues; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor-Derived; Veterans; War; cancer risk; carcinogenesis; cohort; expectation; insight; lung carcinogenesis; nerve agent; oncoprotein p21; tumor

DESCRIPTION (provided by applicant): The employment of chemical weapons by Iraq during the Iran-Iraq War (1980-1988) resulted in over 100,000 military and civilian casualties among Iranians. Both organophosphates (nerve agent) and alkylating compounds (mustards) were used, with mustards being the most-frequently utilized. Mustard gas is a known mutagen and chronic, occupational exposure is carcinogenic in humans. However, it is not dear whether an acute exposure to mustard agent (e.g., in a battlefield or terrorist scenario) is sufficient to initiate lung carcinogenesis. We propose performing a molecular analysis of lung cancers obtained from individuals exposed to mustard gas during the Iran-Iraq War. We will focus on the p53 tumor suppressor gene since the frequency, type and position of p53 mutations are dependent on the nature of the primary carcinogen. Paraffin-embedded lung tumors from mustard-exposed and nonexposed Iranian military veterans and civilians are available for analysis (approximately 50 to 100 per group). A limited set of tissue from cancer-free mustard gas victims is also available from an on-going Iranian study to analyze the p53 mutation load at early stages of carcinogenesis. The following studies are proposed: 1. A sequence analysis of the p53 tumor suppressor gene will be performed on DNA isolated from lung tumor samples from mustard gas-exposed and non-exposed Iranian cohorts. A characteristic mutatidnal fingerprint in tumors from mustard gas victims would implicate mustard gas as the primary carcinogen. 2. p53 status in non-cancer tissue from mustard gas exposed and non-exposed individuals will be determined. This analysis will include an examination of p53 stabilization, down-stream gene activation (p21 and Mdm2 expression) and mutation. The tissue analyzed will be derived from a current Iranian study of mustard gas victims referred to the clinic for hemoptysis evaluation. Successful completion of these studies will help establish mustard gas as the relevant carcinogen in Iranian mustard gas victims, a conclusion that would have associated ethical and legal implications. These studies would also set the groundwork for a more detailed genetic examination of these carcinogen-induced tumors, and could facilitate the development of genetic tests to determine cancer risk in mustard gas victims. Finally, these studies will provide unique insight into the ability of a powerful mutagen to initiate carcinogenesis in humans after a single, high intensity exposure.

伊拉克在两伊战争（1980-1988年）期间使用化学武器，造成伊朗10万多名军人和平民伤亡。有机磷酸盐（神经毒剂）和烷基化化合物（多氯联苯）都被使用，多氯联苯是最常用的。芥子气是一种已知的诱变剂，长期职业接触对人类具有致癌性。然而，急性暴露于芥子剂（例如，中 战场或恐怖场景）足以引发肺癌发生。我们建议对两伊战争期间暴露于芥子气的个体的肺癌进行分子分析。由于p53突变的频率、类型和位置取决于原发性致癌物的性质，因此我们将重点讨论p53肿瘤抑制基因。暴露于芥子气和未暴露于芥子气的伊朗退伍军人和平民的石蜡包埋肺肿瘤可用于分析（每组约50至100例）。一组来自无癌芥子气受害者的有限组织也可从一项正在进行的伊朗研究中获得，以分析癌变早期阶段的p53突变负荷。提出了以下几个方面的研究：1.将对从暴露于芥子气和未暴露于芥子气的伊朗队列的肺肿瘤样本中分离的DNA进行p53肿瘤抑制基因的序列分析。芥子气受害者肿瘤中的特征性突变指纹表明芥子气是主要致癌物。2.将确定来自芥子气暴露和非暴露个体的非癌组织中的p53状态。该分析将包括p53稳定性、下游基因激活（p21和Mdm 2表达）和突变的检查。分析的组织将来自伊朗目前对芥子气受害者的研究，这些受害者被转诊到诊所进行咯血评估。这些研究的成功完成将有助于确定芥子气是伊朗芥子气受害者的相关致癌物，这一结论将产生相关的伦理和法律的影响。这些研究还将为这些致癌物诱导的肿瘤的更详细的基因检查奠定基础，并可能促进基因测试的发展，以确定芥子气受害者的癌症风险。最后，这些研究将提供独特的洞察力，一个强大的诱变剂启动致癌作用后，在人类的能力，单次，高强度的暴露。