Identification and Validation of DNA Methylation Biomarkers for High Grade and/or

高等级和/或 DNA 甲基化生物标志物的鉴定和验证

• 批准号: 8116709
• 负责人: Srinivasan Yegnasubramanian
• 金额: $ 22.37万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8116709
• 关键词: Adjuvant Therapy; Aftercare; Automobile Driving; Binding; Biological Assay; Biological Markers; Caring; Clinical; Clinical Trials; Counseling; CpG Islands; CpG dinucleotide; Cytosine; DNA; DNA Binding; DNA Methylation; Data; Defect; Deletion Mutation; Detection; Development; Diagnosis; Disease; Disease Progression; Epidemiologic Studies; Epidemiology; Epigenetic Process; Figs - dietary; Follow-Up Studies; GSTP1 gene; Genome; Genome Mappings; Genomics; Gold; Health Professional; Hospitals; Human; Hypermethylation; Individual; Laboratories; Lesion; Life; Malignant Neoplasms; Malignant neoplasm of prostate; Medical; Methods; Methylation; Minority; Molecular; Monitor; Morbidity - disease rate; Mutation; Neoplasm Metastasis; Organ; Organ Donor; Patients; Pattern; Physicians; Play; Prevention; Principal Investigator; Prostate; Provider; Recurrence; Recurrent Malignant Neoplasm; Regulator Genes; Research Design; Resolution; Risk; Role; Sampling; Screening for Prostate Cancer; Severity of illness; Site; Specimen; Staging; Stratification; Subgroup; Technology; Testing; Therapeutic; Tissues; Treatment Efficacy; Validation; advanced disease; base; bisulfite; cancer cell; cancer recurrence; cancer risk; case control; cohort; cost; design; disorder later incidence prevention; drug development; follow-up; genome wide association study; genome-wide; genome-wide analysis; high risk; high throughput screening; lymph nodes; malignant phenotype; men; mortality; novel; prevent; programs; prostate carcinogenesis; tumor progression

Prostate cancer recurrence after treatment continues to be the major cause of prostate cancer related morbidity and mortality. Since only a relatively small subset of men that develop prostate cancer will ever progress to life-threatening disease, the development of biomarkers that can reliably predict which men with prostate cancer are likely to develop aggressive and/or recurrent cancer would have tremendous clinical and translational value. The progressive acquisition of somatic genome alterations is a defining feature of all human cancers, including prostate cancer. Cancer cells carry a variety of genetic defects, including mutations, deletions, translocations, and amplifications. More recently, we and others have shown that cancer cells also acquire a number of epigenetic defects, including changes in DMA cytosine methylation patterns, which can have functional equivalence to genetic changes in maintaining malignant phenotypes. For prostate cancer, DNA hypermethylation at CpG islands, one of the most widely studied epigenetic processes, appears to occur in multiple waves. A large initial wave of CpG island hypermethylation appears to occur very early during prostate carcinogenesis, arising at the stage of prostate precursor lesions and maintained throughout disease progression. These early CpG island hypermethylation changes are already under large-scale clinical and translational development as biomarkers for prostate cancer screening and diagnosis. We and others have also collected preliminary evidence suggesting that there are subsequent waves of CpG island hypermethylation in prostate cancer, and that these changes, which may play a role in driving disease progression, may be associated with disease severity (e.g., cancer grade and stage) and/or recurrence after treatment. In this project, we hypothesize that CpG island hypermethylation changes occurring in these susbsequent waves can be exploited as reliable DNA based molecular biomarkers for aggressive (i.e., high grade) and/or recurrent prostate cancer. We plan to undertake the most comprehensive genome-wide search and large-scale epidemiologic study-based validation of such DNA methylation biomarkers in prostate cancer to date in two specific aims. In the first aim, we will carry out a high-resolution, genome-wide characterization of DNA methylation changes in high grade and/or recurrent prostate cancers using a novel genome-wide DNA methylation detection technology developed in our laboratory. In the second aim, we will perform large scale validation of previously known and newly identified DNA methylation changes as biomarkers of high-grade and/or recurrent prostate cancer using two large epidemiologic studies. These studies will evaluate the utility of DNA methylation alterations as biomarkers of prostate cancer risk stratification.

前列腺癌治疗后复发仍然是前列腺癌相关的主要原因 发病率和死亡率。因为只有相对较小一部分罹患前列腺癌的男性 威胁生命的疾病的进展，生物标记物的发展，可以可靠地预测哪些男性患有 前列腺癌很可能发展为侵袭性和/或复发性癌症，具有巨大的临床和 翻译价值。体细胞基因组改变的逐渐获得是所有 人类癌症，包括前列腺癌。癌细胞携带多种基因缺陷，包括 突变、缺失、易位和扩增。最近，我们和其他人已经证明了 癌细胞还获得了一些表观遗传缺陷，包括DMA胞嘧啶甲基化的变化 在维持恶性表型方面，可以与遗传变化具有功能等价性的模式。 对于前列腺癌，CpG岛上的DNA超甲基化，这是最广泛研究的表观遗传学之一 过程，似乎发生在多个浪潮中。出现一大波CpG岛超甲基化 发生在前列腺癌的早期，出现在前列腺癌的前驱病变阶段和 在疾病发展过程中一直保持。这些早期的CpG岛超甲基化变化已经 作为前列腺癌筛查和生物标志物的大规模临床和翻译开发 诊断。我们和其他人也收集了初步证据表明， CpG岛高甲基化在前列腺癌中的波动，以及这些变化，可能在前列腺癌中发挥作用 推动疾病进展，可能与疾病严重程度(例如，癌症分级和分期)和/或 治疗后复发。 在这个项目中，我们假设CpG岛的超甲基化变化发生在这些序列中 WAVE可以被开发为基于DNA的可靠分子生物标志物，用于侵略性(即高级别)和/或 复发性前列腺癌。我们计划进行最全面的全基因组搜索 基于大规模流行病学研究的前列腺癌DNA甲基化生物标志物的验证 日期有两个具体的目标。在第一个目标中，我们将进行高分辨率的全基因组表征 使用一种新的全基因组DNA研究高级别和/或复发前列腺癌的DNA甲基化变化 我们实验室开发的甲基化检测技术。在第二个目标中，我们将进行大规模的 已知和新发现的DNA甲基化变化作为高级别肿瘤生物标志物的有效性 和/或复发性前列腺癌使用两项大型流行病学研究。这些研究将评估 DNA甲基化改变作为前列腺癌风险分层生物标志物的应用。