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a

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.