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

描述（由申请人提供）：由于目前用于区分良性肿块和恶性肾细胞癌（RCCs）的方法通常不准确或不确定，因此肾脏小肿块（SRM）的临床管理具有挑战性。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的和潜在的病态外科手术。长期目标是改善SRM患者的临床管理。本申请的目的是鉴定DNA甲基化标志物，其可以提高肾穿刺活检的诊断价值。中心假设是差异甲基化DNA标记物可用于明确区分恶性和良性SRMs，并补充组织学检查结果，以实现更准确的RCC诊断。拟议研究的基本原理是，由于DNA甲基化的变化可能发生在组织学变化之前，并且可以在少量组织中检测到，因此测量穿刺活检材料中的DNA甲基化标记物将能够识别恶性SRM。该假设将通过追求两个特定目标进行测试：1）选择并验证一组与邻近正常组织和正常肾上皮相比在RCC中差异甲基化的候选标志物;和2）确定这些标志物在针吸活检中区分恶性与良性小肾肿块的灵敏度和特异性。在第一个目标下，将比较匹配的肿瘤和正常组织中的DNA甲基化模式，以确定一组对RCC的三种最常见亚型中的每一种都具有特异性的标志物和一组对RCC通用的标志物。这些标志物将使用不同的定量测定法对一组独立的良性病变和RCC肿瘤与匹配的正常组织进行验证。在第二个目标下，将确认针穿刺活检和匹配的大块肿瘤中存在经验证的标志物作为对照。然后，将来自针穿刺活检的DNA甲基化标记物结果和组织学发现与大块肿瘤的组织病理学特征进行比较，以评价与单独的针穿刺活检的组织学特征相比，该组合方法的灵敏度和特异性。这种方法是创新的，因为它代表了一个显着偏离目前的方法表征SRM。这项研究是有意义的，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。 公共卫生相关性：拟议的研究与公共卫生有关，因为提高肾穿刺活检区分良性小肾肿块和恶性肾细胞癌的准确性将最大限度地减少良性病变患者不必要的手术，降低相关的发病率/死亡率，并更早地识别恶性病变，增加保留肾功能的机会。因此，该项目与NCI的使命以及与改善癌症患者临床管理相关的特定FOA相关。

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.