(Applicant's Description): This competing renewal application requests continued support for a Program Project currently in its 22nd year of funding. The central theme of this program is the role of iatrogenic exposures in the etiology and prevention of cancer. Substantial contributions have been made by the program in terms of understanding the role of exogenous hormones, including oral contraceptives and hormone replacement, in the causation of various human cancers and also in terms of other major health outcomes. Other exposures of great interest to the program over the years include analgesics, diuretics, and low dose medical radiation, surgical procedures including vasectomy and gastrectomy, and cancer therapeutic agents such as tamoxifen. Data generated by this Program Project have had major influences on pharmaceutical formulations, prescribing practices and chemoprevention strategies. The scientific program of the current application consists of three individual projects to be supported by three core resources. The projects include: (1) A study of the relationship between hormone replacement therapy (HRT) and colon cancer risk, including mechanistic studies of DNA methylation of the estrogen receptor gene associated with use of HRT; (2) A study of risk modification by oral contraceptives and other hormonal risk factors on BRCA1-associated breast cancer; and (3) Expansion of an ongoing case control study of low dose medical radiation and morphologic subtypes of acute myelogenous leukemia. Risk modification by ataxia telangiectasia (AT) genotype will also be evaluated. The major core resource of this program project is the Cancer Surveillance Program, a rapid case ascertainment population- based SEER cancer registry providing descriptive data for hypothesis generation as well as case identification. Other core resources include a Control Identification Core for identifying population controls for the individual projects; and a Scientific Leadership and Administrative Core for overseeing scientific direction, coordinating scientific interactions, and conducting the administrative activities required by this program. This program strives for timely identification and evaluation of potential iatrogenic hazards as well as those with possible chemopreventive efficacy. The program has attempted to incorporate new molecular technology for evaluating individual susceptibility following iatrogenic exposures, and also has strived to conduct mechanistic studies to understand the mode of action of iatrogenic carcinogenic exposures at a cellular or molecular level.
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