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）：前列腺癌是一种生长缓慢的疾病，可能涉及一系列环境损害，导致DMA累积损伤，最终导致显性癌变。DNA加合物是人类细胞中为数不多的与癌症直接相关的生物标志物之一，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）的生物有效剂量的可靠测量。表观遗传标记在确定前列腺癌发生程度方面越来越重要。近年来的研究表明，DNA加合物的形成和异常基因启动子的超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从前列腺癌或癌前病变患者身上采集的细胞上。虽然这些研究具有指导意义，但要更清楚地了解DNA加合物形成和前列腺表观遗传变化之间的相互联系和风险，只能从疾病发病前捕获的前列腺组织的研究中获得。在亨利·福特健康系统，我们对5000多名没有前列腺癌的男性进行了特征描述，并有机会接触到这些男性，他们的良性前列腺样本在1990年至2002年间被手术切除。我们计划将该队列扩展到2006年，并将随访队列成员的前列腺癌诊断事件到2010年，以达到800对匹配病例对照的理想研究样本量。基于我们最初资助期的发现，前列腺癌男性前列腺细胞中PAH-和php -DNA加合物的决定因素的特征，在这个竞争的延续中，我们寻求更好地理解DNA加合物与良性前列腺和晚期前列腺癌发展中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一项巢式病例对照研究，该研究将：1)在调整其他可能的混杂因素后，确定PAH-和php - dna加合物是否可预测前列腺癌的晚期发展；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php -DNA加合物与前列腺癌之间的关系；3)确定良性前列腺DNA加合物是否与前列腺癌男性前列腺肿瘤中p53和p21waf/cip1抑癌基因的表达水平相关。