A Nested Case-Control Study of Prostate Carcinogenesis

描述（由申请人提供）：前列腺癌是一种生长缓慢的疾病，可能涉及一系列环境损害，导致累积的 DMA 损伤，最终导致明显的癌变。 DNA 加合物是与癌症直接相关的少数生物标志物之一，可在人体细胞中进行定量，并且是已知致癌物（如多环芳烃 (PAH) 和 2-氨基-1-甲基-6-苯基咪唑[4, 5-b]吡啶 (PhIP)）生物有效剂量的可靠测量方法。表观遗传标记对于确定前列腺癌发生的程度越来越重要。最近的研究表明，DNA 加合物的形成和异常基因启动子高甲基化可能是环境诱发癌发生的相关因素。大多数关于 DNA 加合物、启动子高甲基化和前列腺癌的研究都集中在从患有前列腺癌或癌前病变的患者身上采集的细胞。虽然这些研究具有启发性，但只有通过对疾病发作前捕获的前列腺组织进行研究，才能更清楚地了解与前列腺 DNA 加合物形成和表观遗传变化相关的相互联系和风险。在亨利·福特卫生系统，我们对超过 5000 名没有前列腺癌的男性进行了特征分析，并获得了这些男性的种族多样性，这些男性在 1990 年至 2002 年间通过手术切除了良性前列腺标本。我们计划在 2006 年之前扩大这个队列，并将在 2010 年之前对前列腺癌诊断的队列成员进行跟踪，以达到 800 个匹配的病例对照对的预期研究样本量。基于我们最初资助期间的研究结果，即前列腺癌男性前列腺细胞中 PAH- 和 PhlP-DNA 加合物的决定因素，在这一竞争性的延续中，我们寻求更好地了解良性前列腺和后来的前列腺癌发展中 DNA 加合物与其他表观遗传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巢式病例对照研究，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后期前列腺癌的发展； 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 加合物与前列腺癌之间的关联； 3)确定良性前列腺中的DNA加合物是否与患有前列腺癌的男性前列腺肿瘤中p53和p21waf/cip1肿瘤抑制基因的表达水平相关。

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.