DNA Methylation, Aging, and Prostate Cancer Risk

DNA 甲基化、衰老和前列腺癌风险

• 批准号: 6552892
• 负责人: HERBERT YU
• 金额: $ 22.75万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6552892
• 关键词: African American; CpG islands; DNA; DNA methylation; DNA repair; aging; biomarker; cancer risk; caucasian American; detoxification; enzyme linked immunosorbent assay; human middle age (35-64); human old age (65+); human tissue; insulinlike growth factor; interleukin 6; male; neoplasm /cancer genetics; nucleic acid purification; patient oriented research; prostate neoplasms; racial /ethnic difference; tumor suppressor genes

Since over 70 percent of prostate cancer cases are diagnosed at age 65 years or older, aging is suspected to be involved in the development of the disease. However, little is known about the mechanism underlying the link between aging and prostate cancer risk. Aging is a biological process governed by a series of molecular and biochemical changes, many of which are manifested by abnormal increases or decreases in gene expression. Suppression of gene transcription through DNA methylation is an important mechanism in regulation of gene expression, and DNA methylation in certain genes increases with age. DNA methylation has also been found frequently in cancer, and many genes with important functions against malignant transformation, such as tumor suppressor genes, detoxification genes, and DNA repair genes, are silenced in cancer due to methylation. The parallel of methylation-suppressed gene expression in the elderly and in cancer patients suggests that DNA methylation may explain in part the increased risk of prostate cancer seen in older men. Despite this observation, no epidemiologic evidence exists concerning the hypothesis that age-related systemic increases in DNA methylation in tumor suppressor genes, detoxification genes, and DNA repair genes occur, and that these increases relate to prostate cancer risk. In this proposal, we will examine this hypothesis by determining if: a) CpG island promoter methylation is increased with age in a tumor suppressor gene, a detoxification gene, and a DNA repair gene; b) CpG island methylation in these genes is higher in African-Americans than in Caucasians; c) CpG island methylation in these genes is higher in prostate cancer patients than in age- and race-matched healthy controls; and d) CpG methylation in these genes is associated with other age-related biomarkers. To achieve these goals, we will analyze blood samples collected from 1,697 men who participated in a prostate cancer screening program during 1998-2000. Plasma and peripheral blood cell DNA will be analyzed for DNA methylation using methylation-specific PCR. Plasma biomarkers will be analyzed using ELISA. The findings of this study will provide insights into the possible mechanism between aging and prostate cancer and may lead to development of new markers.

由于超过 70% 的前列腺癌病例是在 65 岁或以上的年龄被诊断出来的，因此人们怀疑衰老与该疾病的发展有关。 然而，人们对衰老与前列腺癌风险之间联系的机制知之甚少。 衰老是一个由一系列分子和生化变化控制的生物过程，其中许多变化表现为基因表达的异常增加或减少。通过DNA甲基化抑制基因转录是基因表达调节的重要机制，某些基因的DNA甲基化随着年龄的增长而增加。 DNA甲基化在癌症中也频繁被发现，许多具有重要抗恶变功能的基因，如抑癌基因、解毒基因、DNA修复基因等，在癌症中因甲基化而沉默。 老年人和癌症患者中甲基化抑制基因表达的相似情况表明，DNA 甲基化可能部分解释了老年男性患前列腺癌的风险增加。 尽管有这一观察结果，但尚无流行病学证据表明肿瘤抑制基因、解毒基因和 DNA 修复基因中 DNA 甲基化与年龄相关的系统性增加，并且这些增加与前列腺癌风险相关。 在本提案中，我们将通过确定是否：a) 肿瘤抑制基因、解毒基因和 DNA 修复基因中的 CpG 岛启动子甲基化随着年龄的增长而增加； b) 这些基因中的 CpG 岛甲基化在非裔美国人中高于白种人； c) 前列腺癌患者中这些基因的 CpG 岛甲基化高于年龄和种族匹配的健康对照； d) 这些基因中的 CpG 甲基化与其他年龄相关生物标志物相关。 为了实现这些目标，我们将分析从 1998 年至 2000 年期间参加前列腺癌筛查计划的 1,697 名男性采集的血液样本。 将使用甲基化特异性 PCR 分析血浆和外周血细胞 DNA 的 DNA 甲基化。 将使用 ELISA 分析血浆生物标志物。 这项研究的结果将深入了解衰老与前列腺癌之间的可能机制，并可能导致新标记物的开发。