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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA167367-01A1
Application #
8384894
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Tricoli, James
Project Start
2012-07-10
Project End
2014-06-30
Budget Start
2012-07-10
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$214,020
Indirect Cost
$83,520
Name
University of Southern California
Department
Urology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Chopra, Sameer; Liu, Jie; Alemozaffar, Mehrdad et al. (2017) Improving needle biopsy accuracy in small renal mass using tumor-specific DNA methylation markers. Oncotarget 8:5439-5448
Helbo, Alexandra Søgaard; Lay, Fides D; Jones, Peter A et al. (2017) Nucleosome Positioning and NDR Structure at RNA Polymerase III Promoters. Sci Rep 7:41947
Becket, Elinne; Chopra, Sameer; Duymich, Christopher E et al. (2016) Identification of DNA Methylation-Independent Epigenetic Events Underlying Clear Cell Renal Cell Carcinoma. Cancer Res 76:1954-64
Lakshminarasimhan, Ranjani; Liang, Gangning (2016) The Role of DNA Methylation in Cancer. Adv Exp Med Biol 945:151-172
Huhdanpaa, Hannu; Hwang, Darryl; Cen, Steven et al. (2015) CT prediction of the Fuhrman grade of clear cell renal cell carcinoma (RCC): towards the development of computer-assisted diagnostic method. Abdom Imaging 40:3168-74
Chopra, Sameer; Satkunasivam, Raj; Kundavaram, Chandan et al. (2015) Outlining the limits of partial nephrectomy. Transl Androl Urol 4:294-300