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Passive smoking, metabolizing genes and female lung cancer

Institution: Childrens Hospital, Los Angeles
Investigator(s): Jan Van Tornout, M.D., M.S.
Award Cycle: 1998 (Cycle 7) Grant #: 7IT-0103 Award: $111,740
Subject Area: Epidemiology
Award Type: Inno Dev & Exp Awards (IDEAS)

Initial Award Abstract
Lung cancer in women is a major health problem. It has recently surpassed breast cancer as the leading cause of cancer death among women. Between 1950 and 1985, there was a 500% increase in lung cancer deaths among women in the United States. The average annual age-adjusted mortality rate for lung cancer among women in Los Angeles County from 19gh 198.4 per 100,000.

Until now it has been extremely difficult to come to a definite scientific conclusion regarding passive smoking. The ‘classically' used methods correlate exposure to environmental tobacco smoke in non-smokers (traditionally spouses of men who smoke) with the risk of developing lung cancer among these subjects. With the small relative risks (RR) for passive smoking typically found in such studies, it is very hard to distinguish between the effect of passive smoke and, for example, the effect of occupational and social exposure to other possible carcinogens (such as automobile exhaust). Thus, a definite causal relationship between lung cancer and PS has not been universally accepted, and additional studies of the same 'classical' design are unlikely to significantly clarify the situation.

Only one in ten smokers will develop lung cancer. Some people are much more 'sensitive' to the effects of tobacco smoke than others. Tobacco smoke contains more than 3000 compounds. Most of these need to be activated by so-called phase I drug metabolizing enzymes (DME) in the body before they become true carcinogens. Moreover, the human body also tries to purify itself from these products by detoxifying them via the so-called phase II DME. Thus, the inter-individual variation in susceptibility to lung cancer could partially be explained by genetic differences (polymorphisms) in these phase I and phase II DME which activate and detoxify the tobacco smoke-derived procarcinogens. Polymorphisms in the phase I and/or phase II DME may modify the risk for developing lung cancer, i.e., if a women has "very active" phase I DME (which activate all the procarcinogens contained in tobacco smoke) and "inactive" detoxifying phase II DME (which fail to clear her body of these carcinogens), she may be at a much higher risk for developing lung cancer following a given exposure to tobacco smoke.

In this study (which is an extension of an already funded molecular epidemiology study), we will analyze the polymorphisms of these phase I and phase II DME among 38with lung cancer who were residing in California at the time of their diagnosis. Through this research, we hope to: (1) elucidate the existing controversies regarding the association between passive smoking and lung cancer risk in women; and, in addition, (2) develop a 'best' and 'worst' genetic risk model for the development of lung cancer in women. Lastly, since this study is an extension of an already funded study, it gathers new information in a cost-effective way by further building on knowledge gathered in previous years working with the same subjects and similar topics.