Characterizing the DNA methylomes of indolent and aggressive prostate cancers

描述（由申请人提供）：在PSA筛查时代，前列腺癌的发病率增加了两倍多，同时根治性前列腺切除术的数量也随之增加。然而，特定原因的死亡率仅略有下降。因此，我们让许多患有生理惰性癌症的患者接受前列腺癌治疗，如根治性前列腺切除术、近距离放疗和外束放射治疗。临床攻击行为的最强预测因子之一是高格里森分级。然而，我们不知道在分子水平上是什么区分低级别和高级别癌症。使用候选基因的方法，DNA甲基化模式的差异已经显示在良性前列腺和前列腺癌之间。更重要的是，我们的初步数据表明，低和高格里森级癌症之间存在广泛的DNA甲基化差异。因此，我们假设DNA甲基化差异是惰性前列腺癌和侵袭性前列腺癌之间生物学差异的基础。在Aim 1中，我们将对良性前列腺癌、低级别癌和高级别癌的DNA甲基化模式进行全基因组定位，以确定低甲基化和高甲基化区域。在目标2中，我们随后将在额外的独立临床标本队列中验证这些差异。目标是利用甲基化差异作为生物标志物，可以区分惰性和侵袭性形式的疾病。最终，这些发现将帮助我们了解惰性前列腺癌和侵袭性前列腺癌之间的基本生物学差异，确定新的生物标志物来区分它们，并为有效治疗提供治疗靶点。

DESCRIPTION (provided by applicant): In the era of PSA screening, the incidence of prostate cancer has increased more than two fold with a concomitant rise in the number of radical prostatectomies performed. However, there has been only a modest decrease in cause-specific mortality. Thus, we are subjecting many patients with biologically indolent cancers to the morbidities of prostate cancer treatments such as radical prostatectomy, brachytherapy, and external beam radiation therapy. One of the strongest predictors of clinically aggressive behavior is high Gleason grade. However, we do not understand at a molecular level what differentiates low grade from high grade cancers. Using a candidate gene approach, differences in DNA methylation patterns have been shown between benign prostate and prostate cancer. More importantly, our preliminary data indicate that there are extensive DNA methylation differences between low and high Gleason grade cancers. Therefore, we hypothesize that DNA methylation differences underlie biological differences between indolent and aggressive prostate cancer. In Aim 1, we will perform a genome-wide mapping of DNA methylation patterns in benign prostate, low grade, and high grade cancers to identify areas of hypo- and hyper- methylation. In aim 2, we will subsequently validate these differences in additional, independent cohorts of clinical specimens. The goal is to utilize methylation differences as biomarkers that can distinguish between indolent and aggressive forms of the disease. Ultimately, these discoveries will help us understand the fundamental biological differences between indolent and aggressive prostate cancer, identify new biomarkers to distinguish them, and provide therapeutic targets for effective treatments.