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以上，同时进行根治性前列腺切除术的数量也增加了。然而，具体原因造成的死亡率仅略有下降。因此，我们正在使许多患有生物学惰性癌症的患者接受前列腺癌治疗的发病率，例如根治性前列腺切除术，近距离放射治疗和外束放射治疗。临床攻击行为的最强预测因子之一是高Gleason分级。然而，我们并不了解在分子水平上是什么区分了低级别和高级别癌症。使用候选基因的方法，在良性前列腺和前列腺癌之间的DNA甲基化模式的差异已被证明。更重要的是，我们的初步数据表明，低和高Gleason分级癌症之间存在广泛的DNA甲基化差异。因此，我们假设DNA甲基化差异是惰性和侵袭性前列腺癌之间生物学差异的基础。在目标1中，我们将对良性前列腺、低级别和高级别癌症中的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样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，可以区分疾病的惰性和侵袭性形式。最终，这些发现将帮助我们了解惰性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.