Using DNA methylation markers to improve the predictive accuracy and utility of needle biopsiesfor determining prostate cancer aggressiveness

项目总结/摘要 一般来说，前列腺癌（PCA）是一种生长缓慢的恶性肿瘤，具有数十年的无痛性，但 呈现出一种侵略性的形式，在一个子集中显示出快速的生长、传播和致命性。 例（< 20%）。因此，在开发预测工具方面存在一个关键的未满足的需求， 在非侵袭性病灶中识别侵袭性PCA病灶。PCA的临床管理是 具有挑战性，因为目前的主动监测方法，以区分侵略性病变， 单灶性或多灶性肿瘤的非侵袭性病变。我们的目标是能够识别 PCA患者的多灶性病变中的侵袭性病变。这将使患者受益 无痛PCA避免了根治性直肠癌切除术，也避免了副作用。长期目标是 使用DNA甲基化生物标志物在早期阶段确定肿瘤的侵袭性，以便 指导临床决定局灶性消融治疗。本申请的目的是 确定DNA甲基化标志物，可以提高前列腺穿刺的诊断价值 活检我们的中心假设是，结合特定的DNA甲基化标记分析， 具有组织学数据的针吸活检将提高对潜在侵袭性肿瘤的诊断准确性。 单灶性或多灶性前列腺癌病变和主动监测。的理由 由于DNA甲基化的变化可以发生在组织学之前， 变化，并可在少量组织中检测到，针中的DNA甲基化标记 活组织检查材料不仅能够识别前列腺癌，而且还能够识别前列腺癌中的侵袭性病变。 多焦点环境我们将通过追求两个具体目标来检验这一假设：1）证实 DNA甲基化改变是否可用于识别侵袭性PCA病变， 主要临床标本中的局灶性或多灶性。这些标志物将在 癌症基因组图谱（TCGA）数据库中的队列; 2）评估鉴定的DNA 目标1中的生物标志物特征在USC前列腺活检样本中的临床适用性 使用来自单灶性或多灶性的超声引导穿刺活检样本队列的储存库 多灶性肿瘤然后，我们将比较穿刺活检中的DNA甲基化标记物结果， 组织病理学特征和患者结局，以评价敏感性， 与单独使用DNA甲基化标记物相比，这种组合方法具有更高的特异性。 这种方法是创新的，因为它与现行方法有很大不同 PCA的攻击性。这项研究的重要性在于， 以显著提高前列腺穿刺活检的诊断准确性。最终，使用 DNA甲基化标志物在诊断侵袭性PCA中的应用将改善患者的生活质量 并通过限制手术干预，同时促进病灶转移， 前列腺癌的治疗

PROJECT SUMMARY/ABSTRACT Generally, Prostate Cancer (PCA) is a slow-growing malignancy with decades of indolence, but takes on an aggressive form displaying rapid growth, dissemination, and lethality in a subset of cases (< 20%). Consequently, a critical unmet need exists in developing prognostic tools to identify aggressive PCA foci among non-aggressive foci. The clinical management of PCA is challenging since the current methods for active surveillance to distinguish aggressive lesion from non-aggressive lesion from unifocal or multifocal tumors. The goal is to be able to identify aggressive lesions from multifocal lesions in PCA patients. This will benefit patients with indolent PCA in avoiding radical prostatectomy as well its side effects. The long-term goal is to determine tumor aggressiveness at an early stage using DNA methylation biomarkers in order to guide clinical decisions on focal ablation therapy. The objective in this particular application is to identify DNA methylation markers that can improve the diagnostic value of prostate needle biopsy. Our central hypothesis is that combining specific DNA methylation marker analyses of needle biopsies with histological data will improve diagnostic accuracy for potentially aggressive unifocal or multifocal prostate cancer lesions and active surveillance. The rationale for the proposed research is that since changes in DNA methylation can occur prior to histological changes and can be detected in small amounts of tissue, DNA methylation markers in needle biopsy material would be able to identify not only prostate cancer, but also aggressive lesions in a multifocal environment. We will test this hypothesis by pursuing two specific aims: 1) to confirm whether DNA methylation alterations can be used to identify aggressive PCA lesions, either focally or multifocally, in primary clinical specimens. These markers will be further validated in the cohort from The Cancer Genome Atlas (TCGA) database; 2) to evaluate the identified DNA biomarker signatures in Aim 1 for their clinical applicability in the USC Prostate Biopsy Sample Repository using a cohort of ultrasound-guided needle biopsy samples from unifocal or multifocal tumors. We will then compare the DNA methylation marker results in needle biopsy to the histopathological profiles and patient outcome in order to evaluate the sensitivity and specificity of this combinatorial approach compared to using DNA methylation markers alone. The approach is innovative because it represents a significant departure from the current method of characterizing PCA aggressiveness. The proposed research is significant because it is expected to considerably increase the diagnostic accuracy of prostate needle biopsies. Ultimately, the use of DNA methylation markers in diagnosing aggressive PCA will improve patient quality of life and reduce the overall health burden by limiting surgical intervention while promoting focal treatment of prostate cancer.