GENE ENVIRONMENT INTERACTIONS IN MESOTHELIOMA

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In Cappadocia, Turkey, there are three villages, Karain, Old Sarihidir, and Tuzkoy, where 50% of deaths are caused by malignant mesothelioma (MM). This incredible epidemic has been linked to exposure to erionite, a type of zeolite fiber. We have established that genetic predisposition plays an important role in this MM epidemics. Our preliminary results demonstrate that in these villages, MM occurs prevalently in certain families and not in others, that'when high-risk MM family members marry into a low risk family, MM appears in the descendents. This finding indicates that genetics play a determining role in this epidemic. However, we also found that MM does not appear to develop in high risk family members born and raised outside these villages. This application is built around the central hypothesis that the epidemic of MM observed in Karain, Tuzkoy and "Old" Sarihidir is caused by the interaction of the environmental carcinogen erionite with genetic predisposition. 'Our hypothesis is that the same gene that is mutated in these Cappadocian families, is the main target of asbestos -and possibly SV40- carcinogenesis in sporadic MM in the Western world. We propose to try to identify the gene/s that predispose to MM in Cappadocia. We also propose to test the hypothesis that the erionite found in these villages has some unique characteristic that makes it more oncogenic compared to the erionite found in Nevada, Oregon, California, and in other parts of the world or to the erionite found in other Cappadocian villages with low or no prevalence of MM. Finally, we will test - in two American MM families we recently identifed - the hypothesis that the same gene that predispose to MM in Cappadocia, contributes to familial MM in the Western world. These studies will be facilitated by the interaction of a multidisciplinary team coordinated by Dr. Carbone, that includes Drs. Baris and Emri (Turkish physicians), Mossman (in vitro mechanistic studies), Testa (array-CGH), Cox (genetic linkage), Steele and Dogan (mineralogy), Pass (Clinical Core).