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，同时进行的根治性前列腺切除术的数量也随之增加。然而，特定原因死亡率仅略有下降。因此，我们让许多患有生物学惰性癌症的患者接受前列腺癌治疗，例如根治性前列腺切除术、近距离放射治疗和外照射治疗。临床攻击行为的最强预测因素之一是高格里森等级。然而，我们不知道在分子水平上如何区分低级别癌症和高级别癌症。使用候选基因方法，良性前列腺癌和前列腺癌之间的 DNA 甲基化模式存在差异。更重要的是，我们的初步数据表明，低格里森级别癌症和高格里森级别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。在目标 1 中，我们将对良性前列腺癌、低级别癌症和高级别癌症的 DNA 甲基化模式进行全基因组图谱分析，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形式和侵袭性形式。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，识别新的生物标志物来区分它们，并为有效治疗提供治疗靶点。 公共健康相关性：没有非侵入性技术可以区分惰性和侵袭性前列腺癌，因此，许多被诊断患有前列腺癌的男性接受侵入性治疗，产生非常不良的副作用，即使我们不确定他们所携带的癌症最终是否会对他们造成伤害。 DNA 甲基化是 DNA 的一种化学修饰，在前列腺癌中，可以阻止细胞中产生看护基因和肿瘤抑制因子，我们假设 DNA 甲基化的变化可以解释前列腺癌侵袭性的差异。该项目的目标是识别区分惰性前列腺癌和侵袭性前列腺癌的 DNA 甲基化标记，从而帮助临床医生决定患者是否需要前列腺癌治疗，并增强我们对该疾病本质的了解。

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. PUBLIC HEALTH RELEVANCE: There are no non-invasive techniques that can distinguish between indolent and aggressive forms of prostate cancer, and therefore, many men diagnosed with prostate cancer undergo invasive treatments with highly undesirable side effects even when we are not sure that the cancer they harbor will ultimately cause them harm. DNA methylation is a chemical modification of DNA that, in prostate cancer, can prevent caretaker genes and tumor suppressors from being manufactured in a cell, and we hypothesize that changes in DNA methylation can account for differences in prostate cancer aggressiveness. The goal of this project is to identify DNA methylation marks that distinguish between indolent and aggressive prostate cancer, thus helping clinicians decide whether a patient needs treatment for prostate cancer and enhancing our understanding of the nature of the disease.