A Nested Case-Control Study of Prostate Carcinogenesis

描述(申请人提供)：前列腺癌是一种发展缓慢的疾病，可能涉及一系列环境侮辱，导致累积的DMA损害，最终导致明显的致癌。DNA加合物是为数不多的可在人体细胞中量化的与癌症直接相关的暴露生物标志物之一，也是多环芳烃(PAH)和2-氨基-1-甲基-6-苯基咪唑并[4，5-b]吡啶(PhIP)等已知致癌物生物有效剂量的可靠衡量标准。表观遗传标记物正在成为决定前列腺癌发生程度的重要指标。最近的研究表明，DNA加合物的形成和基因启动子的异常甲基化可能是环境致癌的相关因素。大多数关于DNA加合物、启动子超甲基化和前列腺癌的研究都集中在前列腺癌或癌前病变患者的细胞上。虽然这些研究具有启发性，但只有在疾病发生前对前列腺组织进行研究，才能更清楚地了解与DNA加合物形成和表观遗传学变化相关的相互联系和风险。在亨利福特健康系统，我们已经确定了一个种族多样化的队列，该队列中有5000多名没有前列腺癌的男性，他们在1990年至2002年期间接受了良性前列腺标本的手术切除。我们计划将这一队列扩大到2006年，并将在2010年之前跟踪前列腺癌诊断的队列成员，以实现800对匹配病例对照的理想研究样本量。在我们最初的资助期发现的基础上，表征了前列腺癌男性前列腺细胞中PAH-和PhlP-DNA加合物的决定因素，在这一竞争的继续中，我们试图更好地理解DNA加合物和良性前列腺癌和后来的前列腺癌发展中的其他表观遗传学变化之间的时间关系。为了实现这一目标，我们计划对前列腺癌进行一项嵌套病例对照研究，该研究将：1)在调整其他可能的混杂因素后，确定PAH-和PhlP-DNA加合物是否可以预测未来前列腺癌的发展；2)在多变量模型中确定异常基因启动子DNA甲基化如何影响PAH-和PhlP-DNA加合物与前列腺癌的关联；以及3)确定良性前列腺中的DNA加合物是否与前列腺癌患者前列腺癌中p53和p21waf/cip1抑癌基因的表达水平有关。

DESCRIPTION (provided by applicant): Prostate Cancer is a slow growing disease that likely involves a series of environmental insults resulting in accumulated DMA damage eventually leading to overt carcinogenesis. DNA adducts are one of the few biomarkers for exposures directly related to cancer that can be quantified in human cells and a reliable measure of biologically effective dose for known carcinogens such as polycyclic aromatic hydrocarbons (PAH) and 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP). Epigenetic markers are emerging as important in determining the extent of prostate carcinogenesis. Recent studies suggest that DNA adduct formation and aberrant gene promoter hypermethylation may be related elements in environmentally-induced carcinogenesis. Most research done with respect to DNA adducts, promoter hypermethylation and prostate cancer has focused on cells harvested from patients with prostate cancer or pre-malignant lesions. While these studies have been instructive, a clearer picture of the interconnection and risk associated with DNA adduct formation and epigenetic changes in prostate can only be gained from studies of prostate tissue captured before the onset of disease. At the Henry Ford Health System, we have characterized and have access to a racially diverse cohort of over five thousand men without prostate cancer from whom benign prostate specimens were surgically removed between 1990 and 2002. We plan to expand this cohort through 2006, and will follow-up cohort members for incident prostate cancer diagnoses through 2010 to achieve a desired study sample size of 800 matched case-control pairs. Building on findings from our initial funding period that characterized determinants of PAH- and PhlP-DNA adducts in the prostate cells of men with prostate cancer, in this competing continuation we seek to better understand the temporal relationship between DNA adducts and other epigenetic changes in the benign prostate and later prostate cancer development. To achieve this objective, we plan to conduct a nested case-control study of prostate cancer that will: 1) determine whether PAH- and PhlP-DNA adducts are predictive of later prostate cancer development after adjusting for other possible confounders; 2) determine in a multivariable model how aberrant gene promoter DNA methylation affects the association between PAH-and PhlP-DNA adducts and prostate cancer; and 3) determine whether DNA adducts in the benign prostate are associated with the level of expression of the p53 and p21waf/cip1 tumor suppressor genes in prostate tumors of men who develop prostate cancer.