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

前列腺癌治疗后复发仍是前列腺癌相关的主要原因 发病率和死亡率。因为只有一小部分患前列腺癌的男性 发展到危及生命的疾病，生物标志物的发展，可以可靠地预测哪些男性与 前列腺癌可能发展为侵袭性和/或复发性癌症， 翻译价值体细胞基因组改变的渐进性获得是所有 人类癌症，包括前列腺癌。癌细胞携带多种遗传缺陷，包括 突变、缺失、易位和扩增。最近，我们和其他人已经表明， 癌细胞还获得了许多表观遗传缺陷，包括DMA胞嘧啶甲基化的变化， 模式，其在维持恶性表型方面与遗传变化具有功能等效性。 对于前列腺癌，CpG岛的DNA超甲基化，是研究最广泛的表观遗传学之一， 过程，似乎发生在多个波。CpG岛高甲基化的初始大波出现 在前列腺癌发生过程中非常早期发生，出现在前列腺前体病变阶段， 在整个疾病进展过程中保持。这些早期的CpG岛高甲基化变化已经被 作为前列腺癌筛查的生物标志物正在进行大规模临床和转化开发， 诊断.我们和其他人也收集了初步证据，表明有随后的 前列腺癌中CpG岛高甲基化的波动，这些变化可能在前列腺癌中发挥作用。 驱动疾病进展，可能与疾病严重程度相关（例如，癌症等级和阶段）和/或 治疗后复发。 在这个项目中，我们假设这些突变体中发生的CpG岛高甲基化改变， 波可以被用作可靠的基于DNA的分子生物标记，用于侵袭性（即，高等级）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对前列腺癌中这类DNA甲基化生物标志物的验证， 有两个具体目标。在第一个目标中，我们将进行高分辨率的全基因组表征， 使用新的全基因组DNA在高级别和/或复发性前列腺癌中的DNA甲基化变化 甲基化检测技术。在第二个目标中，我们将进行大规模的 验证先前已知的和新鉴定的DNA甲基化变化作为高级别恶性肿瘤的生物标志物 和/或复发性前列腺癌。这些研究将评估 DNA甲基化改变作为前列腺癌风险分层的生物标志物的效用。

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.