Mustard Gas Exposure and Carcinogenesis of the Lung

描述（由申请人提供）：伊拉克在两伊战争（1980-1988年）期间使用化学武器，造成10万多名伊朗军人和平民伤亡。使用了有机磷酸盐（神经毒剂）和烷基化化合物（芥菜），其中芥菜是最常用的。芥子气是一种已知的诱变剂，长期职业性接触对人类有致癌作用。然而，急性暴露于芥子气剂（例如，在战场或恐怖活动中）是否足以引发肺癌尚不清楚。我们建议对两伊战争期间暴露于芥子气的个体进行肺癌分子分析。我们将重点关注p53肿瘤抑制基因，因为p53突变的频率、类型和位置取决于原发致癌物的性质。来自芥子气暴露和未暴露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）。伊朗正在进行的一项研究也提供了一组来自无癌症芥子气受害者的有限组织，用于分析癌变早期阶段的p53突变负荷。本文拟进行以下研究：将对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。芥子气受害者肿瘤的特征突变指纹表明芥子气是主要致癌物。2. 将测定暴露于芥子气和未暴露于芥子气的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Mdm2表达）和突变的检查。分析的组织将来自目前伊朗的一项研究，该研究涉及到诊所进行咯血评估的芥子气受害者。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影响。这些研究还将为对这些致癌物诱发的肿瘤进行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见解，以了解在单次高强度暴露后，强大的诱变剂在人体中引发致癌作用的能力。

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 mutational 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.