A Nested Case-Control Study of Prostate Carcinogenesis

前列腺癌发生的巢式病例对照研究

• 批准号: 7426848
• 负责人: Benjamin A. Rybicki
• 金额: $ 58.84万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7426848
• 关键词: 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine; Affect; Aromatic Hydrocarbons; Aromatic Polycyclic Hydrocarbons; Basic Science; Benign; Binding; Biological Markers; CDKN1A gene; Carcinogens; Cells; DNA Adduction; DNA Adducts; DNA Damage; DNA Methylation; Development; Disease; Dose; Environmental Exposure; Epigenetic Process; Funding; Gene Mutation; Genes; Harvest; Health system; Human; Hypermethylation; In Vitro; Indium; Induced Mutation; Investigation; Lead; Lesion; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Modeling; Mutation; Nested Case-Control Study; Onset of illness; Patients; Personal Satisfaction; Polycyclic Hydrocarbons; Premalignant; Prostate; Prostatic Diseases; Prostatic Neoplasms; Rattus; Research; Research Personnel; Risk; Role; Sample Size; Series; Specimen; TP53 gene; Tissues; Tumor Suppressor Genes; Work; cancer diagnosis; cancer risk; carcinogenesis; carcinogenicity; case control; cell transformation; cofactor; cohort; desire; follow-up; in vivo; member; men; mutant; oncoprotein p21; promoter; pyridine

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.

描述（由申请人提供）：前列腺癌是一种缓慢的疾病，可能涉及一系列环境侮辱，从而导致DMA损害累积，最终导致了明显的癌变。 DNA加合物是与癌症直接相关的接触的少数生物标志物之一，可以在人类细胞中进行量化，并且可靠地测量已知的癌剂（如多环芳族氢碳酸盐（PAH）（PAH）和2-氨基-1-氨基-1-甲基-6-甲基-6-苯基胺基胺胺[4，5-b] pyridine（Phip））的生物学有效剂量。表观遗传标记在确定前列腺癌的程度中变得重要。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保诱导的癌变的相关元素。关于DNA加合物，启动子高甲基化和前列腺癌的大多数研究都集中在从前列腺癌或恶性病变患者中收获的细胞上。尽管这些研究具有启发性，但只有从疾病发作之前捕获的前列腺组织的研究中才能获得更清晰的互连和风险相关的互连和风险。在亨利·福特（Henry Ford）的卫生系统中，我们已经进行了表征，并可以使用五千多名男性的种族群体，而没有前列腺癌，从1990年到2002年之间，通过手术删除了良性的前列腺样本。我们计划扩展这一同类群体，并将其扩展到2006年，并将通过2010年的Indistate Prostate Cancer诊断进行随访的同类诊断，以实现800 0000次匹配的型号。基于我们最初的资金期间的发现，这些发现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，在这种竞争延续中，我们试图更好地了解DNA加合物与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嵌套的病例对照研究，该研究将：1）确定PAH-和PHLP-DNA加合物是否可以预测在调整其他可能的混杂因子后将后来的前列腺癌发展； 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p53和p21WAF/CIP1肿瘤抑制剂基因的表达水平有关，这些男性的前列腺肿瘤中的前列腺肿瘤的表达水平。