Genomic and Functional Analysis of Translocation Renal Cell Carcinoma
Abstract
Objective and Rationale: There are over 60,000 new cases of kidney cancer each year in the United States. There are many different subtypes of kidney cancer. About 70% of kidney cancer is so-called clear cell kidney cancer. Over the past several years, there have been many promising treatments approved for clear cell kidney cancer, including targeted therapies and immunotherapies. The other 30% of kidney cancer is called non-clear cell kidney cancer, of which there are multiple different subtypes. Unfortunately, most clinical trials of kidney cancer have excluded patients with non-clear cell kidney cancers. Therefore, we do not know if the therapies approved for clear cell kidney cancer are as effective in patients with non-clear cell kidney cancer; in fact, some studies suggest that they may not be. The most likely explanation for this is that clear cell kidney cancer and non-clear cell kidney cancers have significant molecular differences. One type of non-clear cell kidney (renal) cancer is called translocation renal cell carcinoma. This type of cancer makes up about 1%-5% of all kidney cancers. It is rare but aggressive, and usually strikes younger, female patients. It usually does not respond well to therapies typically used for clear-cell kidney cancer. On the molecular level, translocation renal cell carcinoma has a unique feature, namely, it is characterized by a joining (translocation) between two genes. One of these genes is located on the X chromosome and is called TFE3. The other gene can be any one of several possible partner genes. The protein created by the joining of TFE3 and a partner gene is known as a TFE3 fusion. Interestingly, the TFE3 partner genes are often involved in RNA splicing, a molecular process by which two regions of RNA are brought together before proteins are made. Because translocation renal cell cancer is so rare, it has not been extensively studied. This proposal seeks to answer several fundamental questions about translocation renal cell cancer. First, what are the genes that are mutated or improperly spliced in this rare type of kidney cancer, and how do these differ from the genes that are altered in clear cell kidney cancer? To answer this question, we will perform whole genome sequencing and RNA sequencing on about 25-30 cases of translocation renal cell cancer. Second, how do the TFE3 fusions work to promote translocation renal cell cancer? To answer this question, we will purify the TFE3 fusions from cell lines derived from patients with translocation renal cell cancer. We will study what other proteins these TFE3 fusions bind to, and also determine what regions of the DNA and RNA in a cell these TFE3 fusions bind. Specifically, we will ask the question of whether the biological process of RNA splicing is affected in cells that express TFE3 fusions. Third, what are the therapeutic targets in translocation renal cell cancer, and how do these differ from targets in clear cell kidney cancer? To answer this, we will inhibit every single gene in the genome in three different cell lines derived from patients with translocation kidney cancer. By doing this, we will be able to determine exactly which genes need to be inhibited to result in death of the cancer cells. FY18 KCRP Areas of Emphasis: This project addresses the following areas of emphasis: genetic, chromatin and gene regulation, mechanism of response and resistance, and rare kidney cancers. Innovation: This project will use a number of cutting-edge technologies to profile translocation renal cell cancer. We will also test the novel idea that the biological pathway of RNA splicing may be affected in this disease. If this hypothesis is correct, it would lead to a new pathway that could be targeted in translocation renal cell cancer. Overall, we will produce data that will significantly advance our understanding of the molecular pathways that are important in this rare kidney cance
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910815
Entities
People
- Srinivas R Viswanathan
Organizations
- Dana–Farber Cancer Institute
- United States Army