GENE-ENVIRONMENT INTERACTION IN PROSTATE CANCER

描述(申请人提供)：许多多环芳烃(PAH)通过DNA加合物的形成具有致癌潜力。在乳腺癌和肺癌中，癌症病例和对照组之间以及正常组织和肿瘤组织之间的PAH-DNA加合物水平的差异已经被证明。流行病学研究发现PAH暴露与前列腺癌有关，在前列腺组织中也检测到DNA加合物，但到目前为止还没有努力将追溯的PAH暴露与前列腺癌中PAH-DNA加合物的生物标记物联系起来。我们建议在400例前列腺癌病例中，回顾评估PAH暴露的主要环境来源(例如，饮食、职业、吸烟)和在DNA加合物形成中潜在的重要的介入性遗传因素。这些遗传因素包括负责PAH激活和解毒的外源代谢酶的多态性，以及可以逆转PAH-DNA加合物形成的DNA修复基因。这项拟议的研究将检验暴露于PAH的持续时间、时间和类型的重要性，并测试遗传和病理因素在前列腺DNA加合物形成中的影响。我们拟议的研究设计与研究人员目前在乳腺癌方面所做的工作平行，这些联合努力旨在为荷尔蒙相关癌症的环境病因学提供一条有希望的新路线。这项拟议的研究是NIEHS-Flined研究“前列腺癌中的基因-环境相互作用”(5个角色，011126-02)的补充应用，并将利用参与这项研究的研究人群。我们的结果将为研究人员提供一个框架，在前列腺癌和相关癌症中进行多水平(例如，环境、遗传、生物)风险评估，这些癌症被认为是多环芳烃在致癌途径中发挥主要作用。

DESCRIPTION (provided by applicant): Many polycyclic aromatic hydrocarbons (PAH) have carcinogenic potential through the formation of DNA adducts. Differences in PAH-DNA adduct levels between cancer cases and controls and between normal and tumor tissue has been demonstrated in breast and lung cancer. PAH exposures have been found associated with prostate cancer in epidemiologic studies, and DNA adducts have been detected in prostate tissue, but heretofore no effort has been made to link retrospective PAH exposures with the biomarker of PAH-DNA adducts in the prostate. We propose to retrospectively assess the main environmental sources of PAH exposures (e.g., diet, occupation, smoking) and potentially important intervening genetic factors in DNA adduct formation in 400 prostate cancer cases. These genetic factors include polymorphisms in xenobiotic metabolizing enzymes responsible for PAH activation and detoxification and DNA repair genes that can reverse PAH-DNA adduct formation. The proposed study will examine the importance of duration timing and type of PAH exposure, and test the effects of genetic and pathologic factors, in the formation DNA adducts in the prostate. Our proposed study design parallels work currently being done in breast cancer by study investigators, and these combined efforts are geared to offer a promising new line of investigation into the environmental etiology of hormonally-related cancers. The proposed study is a supplemental application to the NIEHS-flinded study, "Gene-Environment Interaction in Prostate Cancer" (5 ROl ES 011126-02) and will utilize the study population that is be enrolled in this study. Our results will provide researchers with a framework to conduct multi-level (e.g., environmental, genetic, biologic) risk assessment in prostate and related cancers where PAH are thought to play a major role in the carcinogenesis pathway.