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伤，导致累积的DMA损伤，最终导致明显的致癌作用。DNA加合物是与癌症直接相关的少数几种生物标志物之一，可以在人体细胞中定量，也是已知致癌物（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。表观遗传学标记物在确定前列腺癌发生的程度方面越来越重要。最近的研究表明，DNA加合物的形成和异常的基因启动子甲基化可能是环境诱导的癌症发生的相关因素。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前列腺癌或癌前病变患者中采集的细胞上。虽然这些研究具有指导意义，但只有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中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，我们对一个由5000多名没有前列腺癌的男性组成的多种族队列进行了特征描述，并获得了这些男性的资料，这些男性在1990年至2002年期间通过手术切除了良性前列腺标本。我们计划在2006年之前扩大这一队列，并将在2010年之前随访队列成员的前列腺癌诊断，以达到800对匹配病例对照对的预期研究样本量。基于我们最初资助期间的发现，其特征在于前列腺癌男性前列腺细胞中PAH-和PhlP-DNA加合物的决定因素，在这种竞争性的延续中，我们寻求更好地理解DNA加合物与良性前列腺和后来前列腺癌发展中的其他表观遗传变化之间的时间关系。为了实现这一目标，我们计划进行一项前列腺癌的巢式病例对照研究，该研究将：1）确定PAH-和PhlP-DNA加合物在调整其他可能的混杂因素后是否可预测晚期前列腺癌的发展; 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;和3）确定良性前列腺中的DNA加合物是否与发生前列腺癌的男性的前列腺肿瘤中p53和p21 waf/cip 1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.