Identification of a sensitive and specific panel of DNA methylated markers to imp

描述（由申请人提供）：小肾肿块（SRMs）的临床管理具有挑战性，因为目前区分良性肿块和恶性肾细胞癌（rcc）的方法经常是不准确或不确定的。高假阴性率增加了癌症进展的风险，不确定的诊断导致不必要和潜在病态的外科手术。长期目标是改善srm患者的临床管理。在这个特殊的应用目的是鉴定DNA甲基化标记，可以提高肾穿刺活检的诊断价值。中心假设是，差异甲基化的DNA标记可以明确区分恶性和良性srm，并补充组织学发现，以允许更准确的RCC诊断。这项研究的基本原理是，由于DNA甲基化的变化可以在组织学变化之前发生，并且可以在少量组织中检测到，因此测量针活检材料中的DNA甲基化标记物将能够识别恶性srm。这一假设将通过追求两个特定目标来验证：1)选择和验证一组候选标记，这些标记在rcc中与邻近的正常组织和正常肾上皮相比存在差异甲基化；2)确定这些标志物在针活检中鉴别肾小肿块良恶性的敏感性和特异性。在第一个目标下，将比较匹配肿瘤和正常组织中的DNA甲基化模式，以确定一组针对三种最常见的RCC亚型的特异性标记，以及一组针对RCC的一般标记。这些标记物将在一组独立的良性病变和匹配正常组织的RCC肿瘤上使用不同的定量分析来验证。在第二个目标下，在针活检和匹配的大块肿瘤中验证标记物的存在将被确认为对照。然后，将针活检的DNA甲基化标记结果和组织学结果与大块肿瘤的组织病理学特征进行比较，以评估这种组合方法与单独针活检的组织病理学特征相比的敏感性和特异性。该方法是创新的，因为它代表了对当前srm特征描述方法的重大偏离。该研究具有重要意义，因为它有望大大提高肾穿刺活检的诊断准确性。最终，这些知识有可能改善srm患者的临床管理。

DESCRIPTION (provided by applicant): The clinical management of small renal masses (SRMs) is challenging since the current methods for distinguishing between benign masses and malignant renal cell carcinomas (RCCs) are frequently inaccurate or inconclusive. High false negative rates increase the risk of cancer progression and indeterminate diagnoses result in unnecessary and potentially morbid surgical procedures. The long-term goal is to improve the clinical management of patients with SRMs. The objective in this particular application is to identify DNA methylation markers that can improve the diagnostic value of renal needle biopsies. The central hypothesis is that differentially methylated DNA markers can be used definitively distinguish between malignant and benign SRMs and complement histological findings to allow for more accurate RCC diagnosis. 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, measurement of DNA methylation markers in needle biopsy material would be able to identify malignant SRMs. This hypothesis will be tested by pursuing two specific aims: 1) Select and validate a panel of candidate markers that are differentially methylated in RCCs compared to adjacent normal tissues and normal renal epithelia; and 2) Determine the sensitivity and specificity of these markers in distinguishing malignant from benign small renal masses in needle biopsies. Under the first aim, DNA methylation patterns in matched tumors and normal tissues will be compared in order to identify a panel of markers that are specific to each of the three most common subtypes of RCC and a panel that is general to RCC. These markers will be validated using a different quantitative assay on an independent set of benign lesions and RCC tumors with matched normal tissues. Under the second aim, the presence of the validated markers in both needle biopsies and matched bulk tumors will be confirmed as a control. Then the DNA methylation marker results and histological findings from the needle biopsies will be compared with the histopathological profiles of the bulk tumors in order to evaluate the sensitivity and specificity of this combinatoral approach in comparison to histological profiling of the needle biopsies alone. The approach is innovative because it represents a significant departure from the current method of characterizing SRMs. The proposed research is significant because it is expected to considerably increase the diagnostic accuracy of renal needle biopsy. Ultimately, such knowledge has the potential to improve the clinical management of patients with SRMs. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because increasing the accuracy of renal needle biopsies in distinguishing between benign small renal masses and malignant renal cell carcinomas will minimize unnecessary surgical procedures for patients with benign lesions, reduce associated morbidity/mortality, and identify malignant lesions earlier, increasing the chance of preserving renal function. Thus, the project is relevant to the NCI's mission and this specific FOA that pertains to improving the clinical management of cancer patients.