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

鉴定一组敏感且特异的 DNA 甲基化标记以进行导入

• 批准号: 8384894
• 负责人: Gangning Liang
• 金额: $ 21.4万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-10 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384894
• 关键词: Aberrant DNA Methylation; Ablation; Benign; Biological Assay; Biopsy; Cancer Patient; Characteristics; Clinical Management; Complement; DNA; DNA Markers; DNA Methylation; Detection; Diagnosis; Diagnostic; Drops; Excision; Goals; Growth; Imaging technology; In Situ; Incidence; Institutes; Kidney; Knowledge; Lead; Lesion; Malignant - descriptor; Malignant Neoplasms; Measurement; Methods; Microscopic; Mission; Molecular Profiling; Morbidity - disease rate; Needle biopsy procedure; Neoplasm Metastasis; Normal tissue morphology; Operative Surgical Procedures; Outcome; Patients; Pattern; Public Health; Relative (related person); Renal Cell Carcinoma; Renal Mass; Renal carcinoma; Renal function; Research; Risk; Sensitivity and Specificity; Survival Rate; Testing; Tissues; United States; Work; candidate marker; cost effective; diagnostic accuracy; improved; innovation; mortality; renal epithelium; tumor; tumor progression; tumorigenesis

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.

描述（由申请人提供）：小肾脏肿块（SRMS）的临床管理具有挑战性，因为当前区分良性肿块和恶性肾细胞癌（RCC）的方法经常不准确或不确定。高假阴性率会增加癌症进展的风险和不确定的诊断导致不必要的和潜在的病态手术程序。长期目标是改善SRMS患者的临床管理。在此特定应用中的目的是确定可以改善肾针活检诊断值的DNA甲基化标记。中心假设是，差异化甲基化的DNA标记可以确定区分恶性和良性SRMS并补充组织学发现，以允许更准确的RCC诊断。拟议的研究的理由是，由于可以在组织学变化之前发生DNA甲基化的变化，并且可以在少量组织中检测到，因此测量针头活检材料中DNA甲基化标记物将能够鉴定出恶性SRMS。与相邻的正常组织和正常的肾上皮相比，将通过追求两个具体目标来检验该假设：1）选择并验证一组候选标记。 2）确定这些标记在区分针头活检中的良性小肾脏时的灵敏度和特异性。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，以识别一系列标记，这些标记是针对RCC的三种最常见亚型中的每个亚型和一般为RCC的图案。这些标记将在独立的良性病变和具有匹配正常组织的RCC肿瘤上使用不同的定量测定法对这些标记进行验证。在第二个目标下，两针活检和匹配的散装肿瘤中验证的标记的存在将被确认为对照。然后，将DNA甲基化标志物的结果和针刺活检的组织学发现与大量肿瘤的组织病理学特征进行比较，以评估与单独的针刺活检的组织学分析相比，该组合方法的敏感性和特异性。该方法具有创新性，因为它与当前表征SRM的方法有很大的不同。拟议的研究很重要，因为预计它将大大提高肾针活检的诊断准确性。最终，这种知识有可能改善SRMS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，因为提高肾脏针头活检在区分良性小肾脏和恶性肾细胞癌方面的准确性将最大程度地减少良性病变患者的不必要的手术程序，从而减少相关的发病率/减少相关的发病率，并确定较早的恶性病变，从而增加肾脏的机会。因此，该项目与NCI的使命和该特定的FOA有关，与改善癌症患者的临床管理有关。